Thiazolecarboxamides and pyridinecarboxamide compounds useful as pim kinase inhibitors

ABSTRACT

The present disclosure describes thiazole and pyridine carboxamide derivatives, their compositions and methods of use. The compounds inhibit the activity of the Pim kinases and are useful in the treatment of diseases related to the activity of Pim kinases including, e.g., cancer and other diseases.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 16/298,601, filed Mar. 11, 2019, which is a continuation ofU.S. patent application Ser. No. 15/815,255, filed Nov. 16, 2017, nowissued U.S. Pat. No. 10,265,307, issued Apr. 23, 2019, which is acontinuation of U.S. patent application Ser. No. 15/373,923, filed Dec.9, 2016, now issued U.S. Pat. No. 9,849,120, issued Dec. 26, 2017, whichis a continuation of U.S. patent application Ser. No. 14/811,038, filedJul. 28, 2015, now issued U.S. Pat. No. 9,550,765, issued Jan. 24, 2017,which is a continuation of U.S. patent application Ser. No. 14/155,212,filed Jan. 14, 2014, now issued U.S. Pat. No. 9,200,004, issued Dec. 1,2015, and claims the benefit of U.S. Provisional Application No.61/752,897, filed Jan. 15, 2013, U.S. Provisional Application No.61/790,952, filed Mar. 15, 2013, and U.S. Provisional Application No.61/859,118, filed Jul. 26, 2013, the entire disclosures of which areincorporated herein by reference in their entirety.

TECHNICAL FIELD

The present application is concerned with pharmaceutically usefulcompounds. The disclosure provides new compounds as well as theircompositions and methods of use. The compounds inhibit the activity ofPim kinases and are therefore useful in the treatment of diseasesrelated to the activity of Pim kinases including, e.g., cancers andother diseases.

BACKGROUND

Protein kinases regulate diverse biological processes including cellgrowth, survival, differentiation, organ formation, morphogenesis,neovascularization, tissue repair, and regeneration, among others.Protein kinases also play specialized roles in a host of human diseasesincluding cancer. The three members of the Pim kinase family, oneexample of a protein kinase family, were initially identified aspreferential integration sites of Moloney leukemia virus in mouse modelsof cancer. Although possessing modest but measurable oncogenic activityalone, they potentiate pro-proliferative and pro-survival oncogenes,e.g., causing a dramatic acceleration of lymphomagenesis inMyc-transgenic or Bcl2-transgenic mice. Mikkers et al., Nature Genet.,2002, 32, 153-159; Shinto et al., Oncogene, 1995, 11, 1729-35.

The three non-receptor serine/threonine kinases Pim1, Pim2 and Pim3regulate cell proliferation and survival by impacting gene transcriptionand protein translation. Zippo, et al., Nature Cell Biol., 2007, 9,932-44; Schatz, et al., J. Exp. Med., 2011, 208, 1799-1807. As opposedto numerous other protein kinases which require activation byphosphorylation, the Pim kinases are constitutively activated and familymembers have overlapping substrate targets and biological functions,with differences between family members dictated, in part, by theirvaried tissue distribution. Expression of the Pim kinases is induced bycytokines and growth factors. Among the cytokines activating Pim kinaseexpression are cytokines which signal through the JAK/STAT pathway. Pimkinases act in parallel to the PI3K/AKT pathway, and they share severalphosphorylation targets (e.g., pBAD, p4EBP1). Inhibitors of Pim kinasesmay therefore potentiate regimens including inhibitors of either the JAKpathway or the PI3K/AKT pathway.

Overexpression of Pim kinases is detected in a wide variety ofhematologic and solid cancers. Overexpression of various family membershave been noted in multiple myeloma, AML, pancreatic and hepatocellularcancers. Claudio et al., Blood 2002, 100, 2175-86; Amson et al., Proc.Nat. Acad. Sci. USA, 1989, 86, 8857-61; Mizuki et al., Blood, 2003, 101,3164-73; Li et al., Canc. Res., 2006, 66, 6741-7; Fujii et al., Int. J.Canc., 2005, 114, 209-18. Pim1 overexpression is associated with poorprognosis in mantle cell lymphoma, esophageal and head and neck cancers.Hsi et al., Leuk. Lymph., 2008, 49, 2081-90; Liu et al., J. Surg.Oncol., 2010, 102, 683-88; Peltola et al., Neoplasia, 2009, 11, 629-36.Pim2 overexpression is associated with an aggressive clinical course ina subset of DLBCL patients. Gomez-Abad et al., Blood, 2011, 118,5517-27. Overexpression is often seen where Myc is overexpressed and Pimkinases can convey resistance to traditional chemotherapeutic agents andradiation. Chen et al., Blood, 2009, 114, 4150-57; Isaac et al., DrugResis. Updates, 2011, 14, 203-11; Hsu et al., Cancer Lett., 2012, 319,214; Peltola et al., Neoplasia, 2009, 11, 629-36.

As such, these data indicate that inhibition of Pim kinases will beuseful to provide therapeutic benefit in cancer patients.

Data from mice deficient for one or multiple Pim kinase family memberssuggests that pan-Pim inhibitor would have a favorable toxicity profile.Triple knockout mice are viable, but are slightly smaller than theirwild type littermates. Mikkers et al., Mol. Cell. Biol., 2004, 24.6104-15. Since Pim kinases are also involved in a variety of immunologicand inflammatory responses and these indications require drug agentswith fewer side effects, Pim kinase inhibitors are expected to be usefulin treating patients with colitis (Shen et al., Dig. Dis. Sci., 2012,57, 1822-31), peanut allergy (Wang et al., J. All. Clin. Immunol., 2012,130, 932-44), multiple sclerosis and lupus (Davis et al., “SmallMolecule Dual Antagonist of Pim 1 and 3 Kinases Ameliorate ExperimentalAutoimmune Encephalomyelitis”, 26^(th) Congress of the EuropeanCommittee for Treatment and Research in Multiple Sclerosis, 13-16 Oct.2010, Gothenburg, Sweden, Poster P436; Robinson et al., J. Immunol.,2012, 188, 119.9) and rheumatoid arthritis (Yang et al., Immunol. 2010,131, 174-182), and other immunological and inflammatory disorders.

The Pim kinases have therefore been identified as useful targets fordrug development efforts. Swords et al., Curr. Drug Targets, 2011,12(14), 2059-66; Merkel et al., Exp. Opin. Investig. Drugs, 2012, 21,425-38; Morwick et al., Exp. Opin. Ther. Patents, 2010, 20(2), 193-212.

Accordingly, there is a need for new compounds that inhibit Pim kinases.The present application describes new inhibitors of Pim kinases that areuseful for treating diseases associated with the expression or activityof one or more Pim kinases, e.g., cancer and other diseases.

SUMMARY

The present disclosure provides, inter alia, a compound of formula (I):

or a pharmaceutically acceptable salt thereof; wherein the variables areas defined below.

The present disclosure also provides a composition comprising a compoundof formula (I), or a pharmaceutically acceptable salt thereof, and atleast one pharmaceutically acceptable carrier.

The present disclosure also provides methods of treating cancer andother diseases comprising administering to a patient a therapeuticallyeffective amount of a compound of formula (I), or a pharmaceuticallyacceptable salt thereof.

The details of one or more embodiments are set forth in the descriptionbelow. Other features, objects, and advantages will be apparent from thedescription and from the claims.

DETAILED DESCRIPTION

For the terms “e.g.” and “such as,” and grammatical equivalents thereof,the phrase “and without limitation” is understood to follow unlessexplicitly stated otherwise.

As used herein, the singular forms “a,” “an,” and “the” include pluralreferents unless the context clearly dictates otherwise.

As used herein, the term “about” means “approximately” (e.g., plus orminus approximately 10% of the indicated value).

I. Compounds

The present disclosure provides, inter alia, a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

X is C or N;

A, B and D are rings;

the bond

represents a normalized bond within the aromatic ring containing both anN and X, which formally is represented by a C═C bond when X is C and asingle bond when X is N;

ring A is of the formula (A-1) or (A-2):

ring A is of the formula (A-1) or (A-2a):

wherein E¹ and E² are rings;

ring B is a fused 3-7 membered carbocycle or a fused 4-7 memberedheterocycle, each of which is substituted by n substituentsindependently selected from R^(B), wherein n is 0, 1, 2 or 3;

ring D is a C₃₋₇ cycloalkyl group or a 4-10 membered heterocycloalkylgroup, each of which is substituted by k substituents independentlyselected from R^(D), wherein k is 0, 1, 2 or 3;

ring E¹ is selected from C₃₋₇ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, and 5-10 membered heteroaryl, each of which isoptionally substituted by 1, 2 or 3 substituents independently selectedfrom R^(E);

ring E² is selected from C₃₋₇ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, and 5-10 membered heteroaryl, each of which isoptionally substituted by 1, 2 or 3 substituents independently selectedfrom R^(E);

R¹ is selected from H, F and NH₂;

R² is selected from H, halo and CN;

R³ is selected from H, halo and CN;

R⁴ is selected from H, F and NH₂;

each R^(B) is independently selected from Cy^(B), halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a1), SR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), S(O)₂NR^(c1)R^(d1) and oxo; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl substituents of R^(B) areeach optionally substituted with 1, 2 or 3 substituents independentlyselected from Cy^(B), halo, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1)and S(O)₂NR^(c1)R^(d1)

each R^(D) is independently selected from Cy^(D), halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a2), SR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2)NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), S(O)₂NR^(c2)R^(d2) and oxo; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl substituents of R^(D) areeach optionally substituted with 1, 2 or 3 substituents independentlyselected from Cy^(D), halo, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2),NR^(c2)C(O)NR^(c2)R^(d2) NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2)and S(O)₂NR^(c2)R^(d2);

each R^(E) is independently selected from Cy^(E), halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a3), SR^(a3),C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3)NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3) S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), S(O)₂NR^(c3)R^(d3) and oxo; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl of R^(E) are each optionallysubstituted with 1, 2 or 3 substituents independently selected fromCy^(E), halo, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)R^(d3) NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3) and S(O)₂NR^(c3)R^(d3);

Cy^(B), Cy^(D) and Cy^(E) are each independently selected from C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl and 4-10 memberedheterocycloalkyl, each of which is optionally substituted by 1, 2, 3, 4or 5 substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂,OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4)OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), C(═NR^(e4))R^(b4),C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, and 4-10 membered heterocycloalkylsubstituents of Cy^(B), Cy^(D) or Cy^(E) are each optionally substitutedwith 1, 2 or 3 substituents independently selected from halo, C₁₋₄haloalkyl, CN, NO₂, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4),C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4) and S(O)₂NR^(c4)R^(d4);

each R^(a1), R^(b1), R^(c1), R^(d1), R^(a2), R^(b2), R^(c2), R^(d2),R^(a3), R^(b3), R^(c3), R^(d3), R^(a4), R^(b4), R^(c4) and R^(d4) isindependently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, (5-10 membered heteroaryl)-C₁₋₄ alkyl or (4-10membered heterocycloalkyl)-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, (5-10 membered heteroaryl)-C₁₋₄ alkyl and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl is optionally substituted with 1,2, 3, 4 or 5 substituents independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5),C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5) and S(O)₂NR^(c5)R^(d5);

or any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl,3-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆haloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5),C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl and5-6 membered heteroaryl are optionally substituted by 1, 2 or 3substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5) NR^(c5)C(O)NR^(c5)R^(d5),NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5) S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5) andS(O)₂NR^(c5)R^(d5);

or any R^(c2) and R^(d2) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl,C₁₋₆ haloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5) NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5) andS(O)₂NR^(c5)R^(d5), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl and 5-6 membered heteroaryl areoptionally substituted by 1, 2 or 3 substituents independently selectedfrom halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a5),SR^(a5)C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5) andS(O)₂NR^(c5)R^(d5);

or any R^(c3) and R^(d3) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆haloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5),C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5) and S(O)₂NR^(c5)R^(d5), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are optionally substituted by 1, 2 or 3substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(as), SR^(as)C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5) andS(O)₂NR^(c5)R^(d5);

or any R^(c4) and R^(d4) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl,3-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆haloalkyl, halo, CN, OR^(a5), SR^(as), C(O)R^(b5), C(O)NR^(c5)R^(d5),C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5) and S(O)₂NR^(c5)R^(d5), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 3-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are optionally substituted by 1, 2 or 3substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN OR^(a5), SR^(a5)C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5) andS(O)₂NR^(c5)R^(d5);

each R^(a5), R^(b5), R^(c5) and R^(d5) is independently selected from H,C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl and C₂₋₄ alkynyl, wherein saidC₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, is optionally substitutedwith 1, 2 or 3 substituents independently selected from OH, CN, amino,halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;

or any R^(c5) and R^(d5) attached to the same N atom, together with theN atom to which they are attached, form a 3-, 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from OH, CN, amino, halo, C₁₋₆alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄ haloalkyl and C₁₋₄ haloalkoxy; and

each R^(e1), R^(e2), R^(e3), R^(e4) and R^(e5) is independently selectedfrom H, C₁₋₄ alkyl and CN.

In some embodiments, X is C.

In some embodiments, X is N.

In some embodiments, ring B is a fused 3-7 membered carbocycleoptionally substituted by 1, 2 or 3 substituents independently selectedfrom R^(B).

In some embodiments, ring B is a fused benzo ring according to formula(B-1):

wherein n is 0, 1, 2 or 3.

In some embodiments, the compound is according to the following formula(I-1):

wherein n is 0, 1, 2 or 3.

In some such embodiments, n is 0.

In some such embodiments, n is 1.

In some embodiments, ring B is a fused 3-7 membered cycloalkyl ringoptionally substituted by 1, 2 or 3 substituents independently selectedfrom R^(B).

In some embodiments, ring B is a fused 5-membered carbocycle optionallysubstituted by 1, 2 or 3 substituents independently selected from R^(B).

In some embodiments, ring B is according to formula (B-2):

wherein n is 0, 1 or 2.

In some such embodiments, n is 0.

In some such embodiments, n is 1.

In some embodiments, ring B is according to formula (B-3):

wherein m is 0, 1 or 2.

In some such embodiments, m is 0.

In some such embodiments, m is 1.

In some embodiments, the compound is according formula (I-2):

wherein n is 0, 1, 2 or 3.

In some such embodiments, n is 0.

In some such embodiments, n is 1.

In some embodiments, the compound is according formula (I-3):

wherein m is 0, 1 or 2.

In some such embodiments, m is 0.

In some such embodiments, m is 1.

In some embodiments, ring B is a fused 4-7 membered heterocycleoptionally substituted by 1, 2 or 3 substituents independently selectedfrom R^(B).

In some embodiments, ring B is a fused 5-6 membered heteroaryl ring,optionally substituted by 1, 2 or 3 substituents independently selectedfrom R^(B).

In some embodiments, ring B is a fused 4-7 membered heterocycloalkylring optionally substituted by 1, 2 or 3 substituents independentlyselected from R^(B).

In some embodiments, ring B is a fused 5-membered heterocycle optionallysubstituted by 1, 2 or 3 substituents independently selected from R^(B).

In some embodiments, ring B is a fused 5-membered heteroaryl optionallysubstituted by 1, 2 or 3 substituents independently selected from R^(B).

In some embodiments, ring B is a fused 5-membered heterocycloalkyloptionally substituted by 1, 2 or 3 substituents independently selectedfrom R^(B).

In some embodiments, ring B is selected from thieno, pyrrolo,dihydrofuro and pyrazolo, each of which is optionally substituted by 1,2 or 3 substituents independently selected from R^(B).

In some embodiments, the compound can be according to formula (I-4):

wherein m is 0, 1 or 2.

In some such embodiments, m is 0.

In some such embodiments, m is 1.

In some embodiments, the compound can be according to formula (I-5):

wherein m is 0, 1 or 2.

In some such embodiments, m is 0.

In some such embodiments, m is 1.

In some embodiments, the compound can be according to formula (I-6):

wherein n is 0, 1, 2 or 3, and R^(B) can be substituted on the nitrogenof ring B.

In some such embodiments, n is 0.

In some such embodiments, n is 1.

In some embodiments, the compound can be according to formula (I-7):

wherein n is 0, 1, 2 or 3, and R^(B) can be substituted on the nitrogenof ring B.

In some such embodiments, n is 0.

In some such embodiments, n is 1.

In some embodiments, the compound can be according to formula (I-8):

wherein m is 0, 1 or 2.

In some such embodiments, n is 0.

In some such embodiments, n is 1.

In some embodiments, the compound can be according to formula (I-9):

wherein m is 0, 1 or 2, and R^(B) can be substituted on the nitrogen ofring B.

In some such embodiments, m is 0.

In some such embodiments, m is 1.

In some embodiments, ring B is a fused 6-membered heterocycle, eachoptionally substituted by 1, 2 or 3 substituents independently selectedfrom R^(B).

In some embodiments, ring B is a fused 6-membered heteroaryl optionallysubstituted by 1, 2 or 3 substituents independently selected from R^(B).

In some embodiments, ring B is a fused 6-membered heterocycloalkyloptionally substituted by 1, 2 or 3 substituents independently selectedfrom R^(B).

In some embodiments, ring B is according to formula (B-4):

wherein n is 0, 1, 2 or 3 and R^(B) can be substituted on the nitrogenatom of ring B.

In some such embodiments, n is 0.

In some such embodiments, n is 1.

In some embodiments, the compound is according to formula (I-10):

wherein n is 0, 1, 2 or 3 and R^(B) can be substituted on the nitrogenatom of ring B.

In some such embodiments, n is 0.

In some such embodiments, n is 1.

In some embodiments, each R^(B) is independently selected from halo,C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, OR^(a1) and oxo.

In some embodiments, each R^(B) is independently selected from halo,C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, OR^(a1).

In some embodiments, each R^(B) is independently selected from CN, OH,methoxy and oxo.

In some embodiments, each R^(B) is independently selected from CN, OHand methoxy.

In some embodiments, ring B is unsubstituted or substituted by 1substituent selected from RB.

In some embodiments, ring B is unsubstituted.

In some embodiments, ring D is a C₃₋₇ cycloalkyl group optionallysubstituted by 1, 2 or 3 substituents independently selected from RD.

In some embodiments, ring D is a 4-10 membered heterocycloalkyl groupoptionally substituted by 1, 2 or 3 substituents independently selectedfrom RD.

In some embodiments, ring D is a 5-membered or 6-memberedheterocycloalkyl group optionally substituted by 1, 2 or 3 substituentsindependently selected from RD.

In some embodiments, ring D is a pyrrolidine, piperidine or azepane ringoptionally substituted by 1, 2 or 3 substituents independently selectedfrom RD.

In some embodiments, ring D is a piperidine ring optionally substitutedby 1, 2 or 3 substituents independently selected from R^(D).

In some embodiments, a nitrogen atom of ring D forms the bond to theremainder of the molecule.

In some embodiments, each R^(D) is independently selected from halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂,OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2).

In some embodiments, each R^(D) is independently selected from C₁₋₆alkyl, OR^(a2), and NR^(c2)R^(d2).

In some embodiments, each R^(D) is independently selected from methyl,OH, and NH₂.

In some embodiments, ring D is a piperidin-1-yl ring substituted at the3-position by an amino group. Ring D can be, e.g.,3-aminopiperidin-1-yl, 3-amino-4-hydroxypiperidinyl or3-amino-4-hydroxy-5-methylpiperidinyl.

In some embodiments, the configuration of the carbon atom at the3-position of the piperidin-1-yl ring forming ring D is (S) when thecarbon atom at the 2-position of the piperidin-1-yl ring forming ring Dhas a higher Cahn-Ingold-Prelog priority than the carbon atom at the4-position and (R) when the carbon atom at the 4-position of thepiperidin-1-yl ring forming ring D has a higher Cahn-Ingold-Prelogpriority than the carbon atom at the 4-position. Ring D can be, e.g.,(3S)-aminopiperidin-1-yl, (3R,4R)-3-amino-4-hydroxypiperidinyl,(3R,4S)-3-amino-4-hydroxypiperidinyl,(3R,4R,5R)-3-amino-4-hydroxy-5-methylpiperidinyl,(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidinyl,(3R,4S,5R)-3-amino-4-hydroxy-5-methylpiperidinyl or(3R,4S,5S)-3-amino-4-hydroxy-5-methylpiperidinyl.

In some embodiments, the configuration of the carbon atom at the3-position of the piperidin-1-yl ring forming ring D is (R) when thecarbon atom at the 2-position of the piperidin-1-yl ring forming ring Dhas a higher Cahn-Ingold-Prelog priority than the carbon atom at the4-position and (S) when the carbon atom at the 4-position of thepiperidin-1-yl ring forming ring D has a higher Cahn-Ingold-Prelogpriority than the carbon atom at the 4-position. Ring D can be, e.g.,(3R)-aminopiperidin-1-yl, (3S,4S)-3-amino-4-hydroxypiperidinyl,(3S,4R)-3-amino-4-hydroxypiperidinyl,(3S,4R,5R)-3-amino-4-hydroxy-5-methylpiperidinyl,(3S,4R,5S)-3-amino-4-hydroxy-5-methylpiperidinyl,(3S,4S,5R)-3-amino-4-hydroxy-5-methylpiperidinyl or(3S,4S,5S)-3-amino-4-hydroxy-5-methylpiperidinyl.

In some embodiments, ring D is a group of the following formula (D-1):

wherein:

R^(x) is H, C₁₋₆ alkyl or OC(═O)C₁₋₆ alkyl;

R^(y) is H or C₁₋₆ alkyl;

a is 1 or 2;

b is 0, 1 or 2; and

the sum of a and b is 1, 2 or 3.

In some embodiments, ring D is a group of the following formula (D-2):

wherein R^(x), R^(y), a and b are as defined for formula (D-1).

In some embodiments, when ring D is a group of formula (D-1) or (D-2),R^(x) is H.

In some embodiments, when ring D is a group of formula (D-1) or (D-2),R^(y) is H.

In some embodiments, when ring D is a group of formula (D-1) or (D-2), ais 1.

In some embodiments, when ring D is a group of formula (D-1) or (D-2), bis 1.

In some embodiments, ring D is a group of formula (D-2), wherein R^(x)is H, C₁₋₆ alkyl or OC(═O)C₁₋₆ alkyl; R^(y) is H or C₁₋₆ alkyl; a is 1or 2; b is 0, 1 or 2; the sum of a and b is 1, 2 or 3; and Ring D isoptionally substituted by 1 or 2 substitutents independently selectedfrom C₁₋₆ alkyl, OH and C₁₋₆ alkoxy.

In some embodiments, ring D is a group of formula (D-2), wherein: R^(x)is H, C₁₋₆ alkyl; R^(y) is H or C₁₋₆ alkyl; a is 1; b is 1; and Ring Dis optionally substituted by 1 or 2 substitutents independently selectedfrom C₁₋₆ alkyl, OH and C₁₋₆ alkoxy.

In some embodiments, ring D is a group selected from formula(D-3)-(D-19):

In some embodiments, ring D is a group of formula (D-3):

In some embodiments, ring D is a group of formula (D-4):

In some embodiments, ring D is a group of formula (D-5):

In some embodiments, ring A is of the formula (A-1):

In some embodiments, R¹ is selected from H and NH₂.

In some embodiments, ring E¹ is C₆₋₁₀ aryl, which is optionallysubstituted by 1, 2 or 3, substituents independently selected fromR^(E).

In some embodiments, ring E¹ is phenyl optionally substituted by 1, 2 or3, substituents independently selected from R^(E).

In some embodiments, ring E¹ is phenyl that is 2,6-disubstituted bysubstituents independently selected from R^(E).

In some embodiments, ring E¹ is 5-10 membered heteroaryl, which isoptionally substituted by 1, 2 or 3, substituents independently selectedfrom R^(E).

In some embodiments, each R^(E) is independently selected from halo,C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, OR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3) In some embodiments, each R^(E) is independentlyselected from halo.

In some embodiments, ring E¹ is phenyl that is 2,6-dihalo-substituted.

In some embodiments, ring E¹ is 2,6-difluorophenyl.

In some embodiments, ring E¹ is phenyl that is 2,6-dihalo-substitutedand further substituted with one additional substituent, preferably atthe 4-position.

In some embodiments, ring E¹ is phenyl that is 2,6-dihalo-substituted(e.g., 2,4-difluoro-substituted) and further substituted with oneadditional substituent (e.g., at the 4-position), wherein the additionalsubstituent is, e.g., selected from C₁₋₆ alkoxy, C₁₋₆ methanesulfanyl,C₁₋₆ methanesulfinyl, C₁₋₆ methanesulfonyl, C₁₋₆ alkoxy-C₁₋₆ alkylenyl,hydroxy-C₁₋₆ alkylene, or tetrahydro-2H-pyran-3-yloxy, e.g., methoxy,ethoxy, methanesulfonyl, methanesulfonyl, methanesulfonyl, ormethoxymethyl, or 2-hydroxypropan-2-yl.

In some embodiments, ring E¹ is 2,6-difluorophenyl,2,6-difluoro-4-(2-hydroxy-2-propyl)phenyl,2,6-difluoro-4-methanesulfanylphenyl,2,6-difluoro-4-methanesulfinylphenyl,2,6-difluoro-4-methanesulfonylphenyl, 2,6-difluoro-3-methoxyphenyl,2,6-difluoro-4-methoxyphenyl, 2,6-difluoro-4-(methoxymethyl)phenyl, or2,6-difluoro-4-(tetrahydro-2H-pyran-3-yloxy)phenyl.

In some embodiments, G³ is CR³.

In some embodiments, G³ is N.

In some embodiments, ring A is of the formula (A-2):

In some such embodiments, G³ is CR³.

In some such embodiments, G³ is N.

In some embodiments, ring A is of the formula (A-2):

In some embodiments, R² is H or halogen.

In some embodiments, R² is F.

In some embodiments, R³ is H.

In some embodiments, R⁴ is selected from H and NH₂.

In some embodiments, ring E² is C₆₋₁₀ aryl, which is optionallysubstituted by 1, 2 or 3, substituents independently selected fromR^(E).

In some embodiments, ring E² is phenyl optionally substituted by 1, 2 or3, substituents independently selected from R^(E).

In some embodiments, ring E² is phenyl that is 2,6-disubstituted bysubstituents independently selected from R^(E).

In some embodiments, ring E² is 5-10 membered heteroaryl, which isoptionally substituted by 1, 2 or 3, substituents independently selectedfrom R^(E).

In some embodiments, each R^(E) is independently selected from halo,C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, OR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3) S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3) In some embodiments, each R^(E) is independentlyselected from halo.

In some embodiments, ring E² is phenyl that is 2,6-dihalo-substituted.

In some embodiments, ring E² is 2,6-difluorophenyl.

In some embodiments, ring E² is phenyl that is 2,6-dihalo-substitutedand further substituted with one additional substituent, preferably atthe 4-position.

In some embodiments, ring E² is phenyl that is 2,6-dihalo-substituted(e.g., 2,4-difluoro-substituted) and further substituted with oneadditional substituent (e.g., at the 4-position), wherein the additionalsubstituent is, e.g., selected from C₁₋₆ alkoxy, C₁₋₆ methanesulfanyl,C₁₋₆ methanesulfinyl, C₁₋₆ methanesulfonyl, C₁₋₆ alkoxy-C₁₋₆ alkylenyl,hydroxy-C₁₋₆ alkylene, or tetrahydro-2H-pyran-3-yloxy, e.g., methoxy,ethoxy, methanesulfonyl, methanesulfonyl, methanesulfonyl, ormethoxymethyl, or 2-hydroxypropan-2-yl.

In some embodiments, ring E² is 2,6-difluorophenyl,2,6-difluoro-4-(2-hydroxy-2-propyl)phenyl,2,6-difluoro-4-methanesulfanylphenyl,2,6-difluoro-4-methanesulfinylphenyl,2,6-difluoro-4-methanesulfonylphenyl, 2,6-difluoro-3-methoxyphenyl,2,6-difluoro-4-methoxyphenyl, 2,6-difluoro-4-(methoxymethyl)phenyl, or2,6-difluoro-4-(tetrahydro-2H-pyran-3-yloxy)phenyl.

In some embodiments, R^(a1), R^(b1), R^(c1), R^(d1), R^(a2), R^(b2),R^(c2), R^(d2), R^(a3), R^(b3), R^(c3) and R^(d3) are each independentlyH or C₁₋₆ alkyl.

In some embodiments, R^(a4)R^(b4), R^(c4) and R^(d4) are eachindependently H or C₁₋₆ alkyl.

In some embodiments, R^(a5), R^(b5), R^(c5) and R^(d5) are eachindependently H or C₁₋₆ alkyl.

In some embodiments, R^(e1), R^(e2), R^(e3), R^(e4) and R^(e5) are eachindependently H or C₁₋₆ alkyl.

In some embodiments, R^(e1), R^(e2), R^(e3), R^(e4) and R^(e5) are eachH.

In some embodiments, the compound is according to the following formula(II-1):

wherein n is 0, 1, 2 or 3; k is 0, 1, 2 or 3, and R^(B), R^(D) and ringA are as defined above for the compounds of formula (I), or any of theembodiments thereof.

In some embodiments, the compound is according to the following formula(II-2):

wherein n is 0, 1, 2 or 3; and k is 0, 1, 2 or 3, and R^(B), R^(D) andring A are as defined above for the compounds of formula (I), or any ofthe embodiments thereof.

In some embodiments, the compound is according to the following formula(II-3):

wherein m is 0 or 1; and k is 0, 1, 2 or 3, and R^(B), R^(D) and ring Aare as defined above for the compounds of formula (I), or any of theembodiments thereof.

In some embodiments, the compound is according to the following formula(II-4):

wherein m is 0, 1, or 2; and k is 0, 1, 2 or 3, and R^(B), R^(D) andring A are as defined above for the compounds of formula (I), or any ofthe embodiments thereof.

In some embodiments, the compound is according to the following formula(II-5):

wherein m is 0, 1, or 2; and k is 0, 1, 2 or 3, and R^(B), R^(D) andring A are as defined above for the compounds of formula (I), or any ofthe embodiments thereof.

In some embodiments, the compound is according to the following formula(II-6):

wherein n is 0, 1, 2 or 3; and k is 0, 1, 2 or 3, and R^(B), R^(D) andring A are as defined above for the compounds of formula (I), or any ofthe embodiments thereof.

In some embodiments, the compound is according to the following formula(II-7):

wherein n is 0, 1, 2 or 3; and k is 0, 1, 2 or 3, and R^(B), R^(D) andring A are as defined above for the compounds of formula (I), or any ofthe embodiments thereof.

In some embodiments, the compound is according to the following formula(II-8):

wherein m is 0, 1, or 2; and k is 0, 1, 2 or 3, and R^(B), R^(D) andring A are as defined above for the compounds of formula (I), or any ofthe embodiments thereof.

In some embodiments, the compound is according to the following formula(II-9):

wherein m is 0, 1, or 2; and k is 0, 1, 2 or 3, and R^(B), R^(D) andring A are as defined above for the compounds of formula (I), or any ofthe embodiments thereof.

In some embodiments, the compound is according to the following formula(II-10):

wherein n is 0, 1, 2 or 3; and k is 0, 1, 2 or 3, and R^(B), R^(D) andring A are as defined above for the compounds of formula (I), or any ofthe embodiments thereof.

In some embodiments, the compound can be selected from the followingcompounds:

-   5-amino-N-{4-[3-aminopiperidin-1-yl]quinolin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   N-{4-[3-aminopiperidin-1-yl]quinolin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[3-aminopiperidin-1-yl]thieno[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   N-{4-[3-aminopiperidin-1-yl]thieno[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{7-[3-aminopiperidin-1-yl]thieno[3,2-b]pyridin-6-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   N-{7-[3-aminopiperidin-1-yl]thieno[3,2-b]pyridin-6-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[3-aminopiperidin-1-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   N-{4-[3-aminopiperidin-1-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[3-aminopiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   N-{4-[3-aminopiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   N-{4-[3-aminopiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   3-amino-N-{4-[3-aminopiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[3-aminopiperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[3-aminopiperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[3-aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   N-{4-[3-aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[3-aminopiperidin-1l-yl]-7-methoxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[3-aminopiperidin-1l-yl]-7-cyano-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[3-aminopiperidin-1-yl]-7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[3-aminopiperidin-1l-yl]-7-oxo-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   N-{4-[3-aminopiperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[3-aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   3-amino-N-{4-[3-aminopiperidin-1l-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   5-amino-N-{4-[3-amino-4-hydroxypiperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{7-[3-amino-4-hydroxypiperidin-1-yl]thieno[3,2-b]pyridin-6-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[3-aminopiperidin-1-yl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   3-amino-N-{4-[3-aminopiperidin-1-yl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[3-aminopiperidin-1-yl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   5-amino-N-{4-[3-aminopiperidin-1-yl]-1H-pyrazolo[3,4-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   N-{4-[3-aminopiperidin-1-yl]-1H-pyrazolo[3,4-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[3-amino-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   3-amino-N-{4-[3-amino-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[3-amino-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   5-amino-N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   5-amino-N-{4-[3-amino-5-(trifluoromethyl)piperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   N-{4-[3-amino-5-(trifluoromethyl)piperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   5-amino-N-{4-[3-amino-5-(trifluoromethyl)piperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   N-{4-[3-amino-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   3-amino-N-{4-[3-amino-5-methylpiperidin-1l-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   5-amino-N-{4-[3-amino-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   3-amino-N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   5-amino-N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   N-{4-[3-aminopiperidin-1-yl]-7-oxo-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(4-ethoxy-2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   5-amino-N-{4-[3-aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluoro-3-methoxyphenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[3-amino-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluoro-3-methoxyphenyl)-1,3-thiazole-4-carboxamide;-   N-{4-[3-aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[3-amino-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxamide;-   5-amino-N-[4-(3-amino-3-methylpiperidin-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   N-{4-[3-aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(methylthio)phenyl]-5-fluoropyridine-2-carboxamide;-   N-{4-[3-aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(methylsulfinyl)phenyl]-5-fluoropyridine-2-carboxamide;-   N-{4-[3-amino-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(methylsulfinyl)phenyl]-5-fluoropyridine-2-carboxamide;    and-   N-{4-[3-aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(methylsulfonyl)phenyl]-5-fluoropyridine-2-carboxamide;-   3-amino-N-{4-[3-aminopiperidin-1l-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)pyrazine-2-carboxamide;-   N-{4-[3-amino-4-hydroxy-4,5-dimethylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[3-amino-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridine-2-carboxamide;-   N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxamide-   N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridine-2-carboxamide;-   N-{4-[3-amino-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxamide-   N-{4-[3-amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide-   N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-[2,6-difluoro-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]-5-fluoropyridine-2-carboxamide;-   N-{4-[3-amino-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]-5-fluoropyridine-2-carboxamide-   3-amino-N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide-   N-{4-[3-amino-5-(trifluoromethyl)piperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxamide;-   N-{4-[3-amino-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxamide;-   5-amino-N-{4-[3-amino-4-hydroxy-4,5-dimethylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;    and-   5-amino-N-{4-[3-amino-4-hydroxy-4,5-dimethylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide.

In some embodiments, the compound can be selected from the followingcompounds:

-   5-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]quinolin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   N-{4-[(3S)-3-aminopiperidin-1-yl]quinolin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]thieno[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   N-{4-[(3S)-3-aminopiperidin-1-yl]thieno[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{7-[(3S)-3-aminopiperidin-1-yl]thieno[3,2-b]pyridin-6-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   N-{7-[(3S)-3-aminopiperidin-1-yl]thieno[3,2-b]pyridin-6-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   N-{4-[(3S)-3-aminopiperidin-1-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[(3S)-3-aminopiperidin-1l-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   N-{4-[(3S)-3-aminopiperidin-1l-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   N-{4-[(3S)-3-aminopiperidin-1l-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   3-amino-N-{4-[(3S)-3-aminopiperidin-1l-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[(3S)-3-aminopiperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[(3S)-3-aminopiperidin-1l-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[(3S)-3-aminopiperidin-1l-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[(3S)-3-aminopiperidin-1l-yl]-(7R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[(3S)-3-aminopiperidin-1l-yl]-(7S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   N-{4-[(3S)-3-aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   N-{4-[(3S)-3-aminopiperidin-1-yl]-(7R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   N-{4-[(3S)-3-aminopiperidin-1l-yl]-(7S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[(3S)-3-aminopiperidin-1l-yl]-7-methoxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[(3S)-3-aminopiperidin-1l-yl]-(7R)-7-methoxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-(7S)-7-methoxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-7-cyano-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[(3S)-3-aminopiperidin-1l-yl]-(7R)-7-cyano-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[(3S)-3-aminopiperidin-1l-yl]-(7S)-7-cyano-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[(3S)-3-aminopiperidin-1l-yl]-7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[(3S)-3-aminopiperidin-1l-yl]-(7R)-7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[(3S)-3-aminopiperidin-1l-yl]-(7S)-7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[(3S)-3-aminopiperidin-1l-yl]-7-oxo-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   N-{4-[(3S)-3-aminopiperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[(3S)-3-aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[(3S)-3-aminopiperidin-1-yl]-(7R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[(3S)-3-aminopiperidin-1-yl]-(7S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   3-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   3-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-(7R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   3-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-(7S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   5-amino-N-{4-[(3R,4R)-3-amino-4-hydroxypiperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[(3S,4S)-3-amino-4-hydroxypiperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[(3R,4S)-3-amino-4-hydroxypiperidin-1l-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[(3S,4R)-3-amino-4-hydroxypiperidin-1l-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{7-[(3R,4R)-3-amino-4-hydroxypiperidin-1-yl]thieno[3,2-b]pyridin-6-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{7-[(3R,4S)-3-amino-4-hydroxypiperidin-1-yl]thieno[3,2-b]pyridin-6-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   3-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[(3S)-3-aminopiperidin-1-yl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   5-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-1H-pyrazolo[3,4-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   N-{4-[(3S)-3-aminopiperidin-1-yl]-1H-pyrazolo[3,4-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-(7R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-(7S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   3-amino-N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   5-amino-N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   5-amino-N-{4-[(3S,5R)-3-amino-5-(trifluoromethyl)piperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-(trifluoromethyl)piperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   5-amino-N-{4-[(3S,5R)-3-amino-5-(trifluoromethyl)piperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[(3S,5R)-3-amino-5-(trifluoromethyl)piperidin-1-yl]-(7R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[(3S,5R)-3-amino-5-(trifluoromethyl)piperidin-1-yl]-(7S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-(7R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-(7S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   3-amino-N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   3-amino-N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-(7R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   3-amino-N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-(7S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   5-amino-N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-(7R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-(7S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   3-amino-N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   3-amino-N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-(7R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   3-amino-N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-(7S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   5-amino-N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-(7R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-(7S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   N-{4-[(3S)-3-aminopiperidin-1-yl]-7-oxo-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(4-ethoxy-2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-(7R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(4-ethoxy-2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-(7S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(4-ethoxy-2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   5-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluoro-3-methoxyphenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[(3S)-3-aminopiperidin-1l-yl]-(7R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluoro-3-methoxyphenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[(3S)-3-aminopiperidin-1l-yl]-(7S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluoro-3-methoxyphenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluoro-3-methoxyphenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-(7R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluoro-3-methoxyphenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-(7S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluoro-3-methoxyphenyl)-1,3-thiazole-4-carboxamide;-   N-{4-[(3S)-3-aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[(3S)-3-aminopiperidin-1-yl]-(7R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[(3S)-3-aminopiperidin-1l-yl]-(7S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-(7R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-(7S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxamide;-   5-amino-N-[4-((3R)-3-amino-3-methylpiperidin-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   5-amino-N-[4-((3S)-3-amino-3-methylpiperidin-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;-   N-{4-[(3S)-3-aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(methylthio)phenyl]-5-fluoropyridine-2-carboxamide;-   N-{4-[(3S)-3-aminopiperidin-1-yl]-(7R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(methylthio)phenyl]-5-fluoropyridine-2-carboxamide;-   N-{4-[(3S)-3-aminopiperidin-1l-yl]-(7S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(methylthio)phenyl]-5-fluoropyridine-2-carboxamide;-   N-{4-[(3S)-3-aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(methylsulfinyl)phenyl]-5-fluoropyridine-2-carboxamide;-   N-{4-[(3S)-3-aminopiperidin-1-yl]-(7R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(methylsulfinyl)phenyl]-5-fluoropyridine-2-carboxamide;-   N-{4-[(3S)-3-aminopiperidin-1-yl]-(7S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(methylsulfinyl)phenyl]-5-fluoropyridine-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(methylsulfinyl)phenyl]-5-fluoropyridine-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-(7R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(methylsulfinyl)phenyl]-5-fluoropyridine-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-(7S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(methylsulfinyl)phenyl]-5-fluoropyridine-2-carboxamide;-   N-{4-[(3S)-3-aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(methylsulfonyl)phenyl]-5-fluoropyridine-2-carboxamide;-   N-{4-[(3S)-3-aminopiperidin-1-yl]-(7R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(methylsulfonyl)phenyl]-5-fluoropyridine-2-carboxamide;-   N-{4-[(3S)-3-aminopiperidin-1-yl]-(7S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(methylsulfonyl)phenyl]-5-fluoropyridine-2-carboxamide;-   3-amino-N-{4-[(3S)-3-aminopiperidin-1l-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)pyrazine-2-carboxamide;-   3-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-(7R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)pyrazine-2-carboxamide;-   3-amino-N-{4-[(3S)-3-aminopiperidin-1l-yl]-(7S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)pyrazine-2-carboxamide;-   N-{4-[(3R,5S)-3-amino-4-hydroxy-4,5-dimethylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-4,5-dimethylpiperidin-1-yl]-(7R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[(3R,4S,5S)-3-amino-4-hydroxy-4,5-dimethylpiperidin-1-yl]-(7R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-4,5-dimethylpiperidin-1-yl]-(7S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[(3R,4S,5S)-3-amino-4-hydroxy-4,5-dimethylpiperidin-1-yl]-(7S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridine-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-(7R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridine-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-(7S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridine-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridine-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-(7R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridine-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-(7S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridine-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-(7R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-(7S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]-(7R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]-(7S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-[2,6-difluoro-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]-5-fluoropyridine-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]-5-fluoropyridine-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-(7R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]-5-fluoropyridine-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-(7S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]-5-fluoropyridine-2-carboxamide;-   3-amino-N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-(trifluoromethyl)piperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-(trifluoromethyl)piperidin-1-yl]-(7R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-(trifluoromethyl)piperidin-1-yl]-(7S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxamide;-   5-amino-N-{4-[(3R,4S,5S)-3-amino-4-hydroxy-4,5-dimethylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide;    and-   5-amino-N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-4,5-dimethylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment (while theembodiments are intended to be combined as if written in multiplydependent form). Conversely, various features of the invention whichare, for brevity, described in the context of a single embodiment, canalso be provided separately or in any suitable subcombination. Thus, itis contemplated that features described as embodiments of the compoundsof formula (I) can be combined in any suitable combination.

At various places in the present specification, certain features of thecompounds are disclosed in groups or in ranges. It is specificallyintended that such a disclosure include each and every individualsubcombination of the members of such groups and ranges. For example,the term “C₁₋₆ alkyl” is specifically intended to individually disclose(without limitation) methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, and C₆alkyl.

The term “n-membered,” where n is an integer, typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

At various places in the present specification, variables definingdivalent linking groups are described. It is specifically intended thateach linking substituent include both the forward and backward forms ofthe linking substituent. For example, —NR(CR′R″)_(n)— includes both—NR(CR′R″)_(n)— and —(CR′R″)_(n)NR— and is intended to disclose each ofthe forms individually. Where the structure requires a linking group,the Markush variables listed for that group are understood to be linkinggroups. For example, if the structure requires a linking group and theMarkush group definition for that variable lists “alkyl” or “aryl” thenit is understood that the “alkyl” or “aryl” represents a linkingalkylene group or arylene group, respectively.

The term “substituted” means that an atom or group of atoms formallyreplaces hydrogen as a “substituent” attached to another group. The term“substituted”, unless otherwise indicated, refers to any level ofsubstitution, e.g., mono-, di-, tri-, tetra- or penta-substitution,where such substitution is permitted. The substituents are independentlyselected, and substitution may be at any chemically accessible position.It is to be understood that substitution at a given atom is limited byvalency. The phrase “optionally substituted” means unsubstituted orsubstituted. The term “substituted” means that a hydrogen atom isremoved and replaced by a substituent. A single divalent substituent,e.g., oxo, can replace two hydrogen atoms.

The term “C_(n-m)” indicates a range which includes the endpoints,wherein n and m are integers and indicate the number of carbons.Examples include C₁₋₄, C₁₋₆ and the like.

The term “alkyl” employed alone or in combination with other terms,refers to a saturated hydrocarbon group that may be straight-chain orbranched. The term “C_(n-m) alkyl”, refers to an alkyl group having n tom carbon atoms. An alkyl group formally corresponds to an alkane withone C—H bond replaced by the point of attachment of the alkyl group tothe remainder of the compound. In some embodiments, the alkyl groupcontains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl moietiesinclude, but are not limited to, chemical groups such as methyl, ethyl,n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higherhomologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl,1,2,2-trimethylpropyl and the like.

The term “alkenyl” employed alone or in combination with other terms,refers to a straight-chain or branched hydrocarbon group correspondingto an alkyl group having one or more double carbon-carbon bonds. Analkenyl group formally corresponds to an alkene with one C—H bondreplaced by the point of attachment of the alkenyl group to theremainder of the compound. The term “C_(n-m) alkenyl” refers to analkenyl group having n to m carbons. In some embodiments, the alkenylmoiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Example alkenylgroups include, but are not limited to, ethenyl, n-propenyl,isopropenyl, n-butenyl, sec-butenyl and the like.

The term “alkynyl” employed alone or in combination with other terms,refers to a straight-chain or branched hydrocarbon group correspondingto an alkyl group having one or more triple carbon-carbon bonds. Analkynyl group formally corresponds to an alkyne with one C—H bondreplaced by the point of attachment of the alkyl group to the remainderof the compound. The term “C_(n-m) alkynyl” refers to an alkynyl grouphaving n to m carbons. Example alkynyl groups include, but are notlimited to, ethynyl, propyn-1-yl, propyn-2-yl and the like. In someembodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3carbon atoms.

The term “alkylene”, employed alone or in combination with other terms,refers to a divalent alkyl linking group. An alkylene group formallycorresponds to an alkane with two C—H bond replaced by points ofattachment of the alkylene group to the remainder of the compound. Theterm “C_(n-m) alkylene” refers to an alkylene group having n to m carbonatoms. Examples of alkylene groups include, but are not limited to,ethan-1,2-diyl, propan-1,3-diyl, propan-1,2-diyl, butan-1,4-diyl,butan-1,3-diyl, butan-1,2-diyl, 2-methyl-propan-1,3-diyl and the like.

The term “alkoxy”, employed alone or in combination with other terms,refers to a group of formula —O-alkyl, wherein the alkyl group is asdefined above. The term “C_(n-m) alkoxy” refers to an alkoxy group, thealkyl group of which has n to m carbons. Example alkoxy groups includemethoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy andthe like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1to 3 carbon atoms.

The terms “halo” or “halogen”, used alone or in combination with otherterms, refers to fluoro, chloro, bromo and iodo.

The term “haloalkyl” as used herein refers to an alkyl group in whichone or more of the hydrogen atoms has been replaced by a halogen atom.The term “C_(n-m) haloalkyl” refers to a C-m alkyl group having n to mcarbon atoms, and from at least one up to {2(n to m)+1}halogen atoms,which may either be the same or different. In some embodiments, thehalogen atoms are fluoro atoms. In some embodiments, the haloalkyl grouphas 1 to 6 or 1 to 4 carbon atoms. Example haloalkyl groups include CF₃,C₂F₅, CHF₂, CCl₃, CHCl₂, C₂Cl₅ and the like. In some embodiments, thehaloalkyl group is a fluoroalkyl group.

The term “haloalkoxy”, employed alone or in combination with otherterms, refers to a group of formula —O-haloalkyl, wherein the haloalkylgroup is as defined above. The term “C_(n-m) haloalkoxy” refers to ahaloalkoxy group, the haloalkyl group of which has n to m carbons.Example haloalkoxy groups include trifluoromethoxy and the like. In someembodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

The term “amino” refers to a group of formula —NH₂.

The term “carbamyl” refers to a group of formula —C(═O)NH₂.

The term “carbonyl”, employed alone or in combination with other terms,refers to a —C(═O)— group, which also may be written as C(O).

The term “carboxy” refers to a group of formula —C(═O)OH.

The term “oxo” refers to oxygen as a divalent substituent, forming acarbonyl group, or attached to a heteroatom forming a sulfoxide orsulfone group, or an N-oxide group.

The term “aromatic” refers to a carbocycle or heterocycle having one ormore polyunsaturated rings having aromatic character (i.e., having(4n+2) delocalized π (pi) electrons where n is an integer).

The term “aryl,” employed alone or in combination with other terms,refers to an aromatic hydrocarbon group, which may be monocyclic orpolycyclic (e.g., having 2, 3 or 4 fused rings). The term “C_(n-m) aryl”refers to an aryl group having from n to m ring carbon atoms. Arylgroups include, e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl,indanyl, indenyl and the like. In some embodiments, aryl groups havefrom 6 to about 20 carbon atoms, from 6 to about 15 carbon atoms, orfrom 6 to about 10 carbon atoms. In some embodiments, the aryl group isphenyl.

The term “heteroaryl” or “heteroaromatic”, employed alone or incombination with other terms, refers to a monocyclic or polycyclicaromatic heterocycle having at least one heteroatom ring member selectedfrom sulfur, oxygen, and nitrogen. In some embodiments, the heteroarylring has 1, 2, 3 or 4 heteroatom ring members independently selectedfrom nitrogen, sulfur and oxygen. In some embodiments, any ring-formingN in a heteroaryl moiety can be an N-oxide. In some embodiments, theheteroaryl has 5-10 ring atoms including carbon atoms and 1, 2, 3 or 4heteroatom ring members independently selected from nitrogen, sulfur andoxygen. In some embodiments, the heteroaryl has 5-6 ring atoms and 1 or2 heteroatom ring members independently selected from nitrogen, sulfurand oxygen. In some embodiments, the heteroaryl is a five-membered orsix-membered heteroaryl ring. Example heteroaryl groups include, but arenot limited to, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole,pyrazole, azolyl, oxazole, thiazole, imidazole, furan, thiophene,quinoline, isoquinoline, indole, benzothiophene, benzofuran,benzisoxazole, imidazo[1,2-b]thiazole, imidazo[1,2-b]pyridazine, purine,furopyridine (e.g., furo[3,2-b]pyridine), thienopyridine (e.g.thieno[3,2-b]pyridine) or the like.

A five-membered heteroaryl ring is a heteroaryl group having five ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O, and S. Exemplary five-membered ring heteroarylsinclude thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl,pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl,1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl,1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

A six-membered heteroaryl ring is a heteroaryl group having six ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O, and S. Exemplary six-membered ring heteroaryls arepyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.

The term “cycloalkyl”, employed alone or in combination with otherterms, refers to a non-aromatic, saturated, monocyclic, bicyclic orpolycyclic hydrocarbon ring system, including cyclized alkyl and alkenylgroups. The term “C_(n-m) cycloalkyl” refers to a cycloalkyl that has nto m ring member carbon atoms. Cycloalkyl groups can include mono- orpolycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles.Cycloalkyl groups can have 3, 4, 5, 6 or 7 ring-forming carbons (C₃₋₇).In some embodiments, the cycloalkyl group has 3 to 6 ring members, 3 to5 ring members, or 3 to 4 ring members. In some embodiments, thecycloalkyl group is monocyclic. In some embodiments, the cycloalkylgroup is monocyclic or bicyclic. In some embodiments, the cycloalkylgroup is a C₃₋₆ monocyclic cycloalkyl group. Ring-forming carbon atomsof a cycloalkyl group can be optionally substituted by oxo or sulfido.Cycloalkyl groups also include cycloalkylidenes. Example cycloalkylgroups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cyclopentenyl, cyclohexenyl, cyclohexadienyl, norbornyl, norpinyl,bicyclo[2.1.1]hexanyl, bicyclo[1.1.1]pentanyl and the like. In someembodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl. Also included in the definition of cycloalkyl are moietiesthat have one or more aromatic rings fused (i.e., having a bond incommon with) to the cycloalkyl ring, e.g., benzo or thienyl derivativesof cyclopentane, cyclohexane and the like. A cycloalkyl group containinga fused aromatic ring can be attached through any ring-forming atomincluding a ring-forming atom of the fused aromatic ring.

The term “heterocycloalkyl”, employed alone or in combination with otherterms, refers to non-aromatic ring or ring system, which may optionallycontain one or more alkenylene groups as part of the ring structure,which has at least one heteroatom ring member independently selectedfrom nitrogen, sulfur oxygen and phosphorus, and which has 4-10 ringmembers 4-7 ring members or 4-6 ring members. Included inheterocycloalkyl are monocyclic 4-, 5-, 6-, and 7-memberedheterocycloalkyl groups. Heterocycloalkyl groups can include mono- orbicyclic (e.g., having two fused or bridged rings) ring systems. In someembodiments, the heterocycloalkyl group is a monocyclic group having 1,2 or 3 heteroatoms independently selected from nitrogen, sulfur andoxygen. Ring-forming carbon atoms and heteroatoms of a heterocycloalkylgroup can be optionally substituted by oxo or sulfido (e.g., C(═O),S(═O), C(═S), or S(═O)₂, etc.) or a nitrogen atom can be quaternized.The heterocycloalkyl group can be attached through a ring-forming carbonatom or a ring-forming heteroatom. In some embodiments, theheterocycloalkyl group contains 0 to 3 double bonds. In someembodiments, the heterocycloalkyl group contains 0 to 2 double bonds.Also included in the definition of heterocycloalkyl are moieties thathave one or more aromatic rings fused (i.e., having a bond in commonwith) to the heterocycloalkyl ring, e.g., benzo or thienyl derivativesof piperidine, morpholine, azepine, etc. A heterocycloalkyl groupcontaining a fused aromatic ring can be attached through anyring-forming atom including a ring-forming atom of the fused aromaticring. Examples of heterocycloalkyl groups include azepane, azetidine,diazepan (e.g., 1,4-diazepan), dihydrobenzofuran, dihydrofuran,dihydropyran, piperazine, piperidine, pyrrolidine, pyran, morpholine,tetrahydropyran, tetrahydrofuran, 1, 2, 3, 4-tetrahydroquinoline,thiomorpholine, and the like.

The term “carbocycle” refers to an aryl group or a cycloalkyl group.

The term “heterocycle” refers to a heteroaryl group or aheterocycloalkyl group.

At certain places, the definitions or embodiments refer to specificrings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached to any ring member provided thatthe valency of the atom is not exceeded. For example, an azetidine ringmay be attached at any position of the ring, whereas an azetidin-3-ylring is attached at the 3-position.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiasteroisomers, are intended unless otherwise indicated. Compounds ofthe present invention that contain asymmetrically substituted carbonatoms can be isolated in optically active or racemic forms. Methods onhow to prepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. One method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, e.g., optically active acids,such as the D and L forms of tartaric acid, diacetyltartaric acid,dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or thevarious optically active camphorsulfonic acids such as β-camphorsulfonicacid. Other resolving agents suitable for fractional crystallizationmethods include stereoisomerically pure forms of α-methylbenzylamine(e.g., S and R forms, or diastereoisomerically pure forms),2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

In some embodiments, the compounds of the invention have the(R)-configuration. In other embodiments, the compounds have the(S)-configuration. In compounds with more than one chiral centers, eachof the chiral centers in the compound may be independently (R) or (S),unless otherwise indicated.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, enamine-imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system,e.g., 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium.

The term, “compound,” as used herein is meant to include allstereoisomers, geometric isomers, tautomers and isotopes of thestructures depicted.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,hydrates and solvates) or can be isolated. When in the solid state, thecompounds described herein and salts thereof may occur in various formsand may, e.g., take the form of solvates, including hydrates. Thecompounds may be in any solid state form, such as a polymorph orsolvate, so unless clearly indicated otherwise, reference in thespecification to compounds and salts thereof should be understood asencompassing any solid state form of the compound.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, e.g., a composition enriched in the compounds of the invention.Substantial separation can include compositions containing at leastabout 50%, at least about 60%, at least about 70%, at least about 80%,at least about 90%, at least about 95%, at least about 97%, or at leastabout 99% by weight of the compounds of the invention, or salt thereof.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The expressions, “ambient temperature” and “room temperature,” as usedherein, are understood in the art, and refer generally to a temperature,e.g., a reaction temperature, that is about the temperature of the roomin which the reaction is carried out, e.g., a temperature from about 20°C. to about 30° C.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. The term “pharmaceutically acceptablesalts” refers to derivatives of the disclosed compounds wherein theparent compound is modified by converting an existing acid or basemoiety to its salt form. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, mineral or organic acid salts of basicresidues such as amines; alkali or organic salts of acidic residues suchas carboxylic acids; and the like. The pharmaceutically acceptable saltsof the present invention include the non-toxic salts of the parentcompound formed, e.g., from non-toxic inorganic or organic acids. Thepharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, alcohols (e.g., methanol, ethanol,iso-propanol, or butanol) or acetonitrile (MeCN) are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17^(th)Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J.Pharm. Sci., 1977, 66(1), 1-19, and in Stahl et al., Handbook ofPharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). Insome embodiments, the compounds described herein include the N-oxideforms.

The following abbreviations may be used herein: AcOH (acetic acid); Ac₂O(acetic anhydride); aq. (aqueous); atm. (atmosphere(s)); Boc(t-butoxycarbonyl); BOP((benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate); br (broad); Cbz (carboxybenzyl); calc.(calculated); d (doublet); dd (doublet of doublets); DCM(dichloromethane); DIAD (N,N′-diisopropyl azodicarboxylate); DIC(N,N′-diisopropylcarbodiimide); DIPEA (N,N-diisopropylethylamine); DMAP(4-dimethylaminopyridine); DMF (N,N-dimethylformamide); Et (ethyl);EtOAc (ethyl acetate); EtOH (ethanol); Fmoc(9-fluorenylmethylmethoxycarbonyl); g (gram(s)); h (hour(s)); HATU(N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate); HCl (hydrochloric acid); HPLC (high performanceliquid chromatography); Hz (hertz); i-Pr (isopropyl); J (couplingconstant); K₃PO₄ (potassium phosphate); LCMS (liquid chromatography-massspectrometry); m (multiplet); M (molar); mCPBA (3-chloroperoxybenzoicacid); Me (methyl); MeCN (acetonitrile); MeOH (methanol); mg(milligram(s)); MgSO₄ (magnesium sulfate); min. (minutes(s)); mL(milliliter(s)); mmol (millimole(s)); MS (Mass spectrometry); N(normal); NaHCO₃ (sodium bicarbonate); NaOH (sodium hydroxide); Na₂SO₄(sodium sulfate); Na₂S₂O₃ (sodium thiosulfate); n-Bu (n-butyl); n-BuLi(n-butyllithium); NH₄Cl (ammonium chloride); NH₄OH (ammonium hydroxide);nM (nanomolar); NMR (nuclear magnetic resonance spectroscopy); Pd(palladium); pM (picomolar); POCl₃ (phosphoryl chloride); PTFE(polytetrafluoroethylene); RP-HPLC (reverse phase high performanceliquid chromatography); s (singlet); t (triplet or tertiary); tert(tertiary); tt (triplet of triplets); t-Bu (tert-butyl); TFA(trifluoroacetic acid); THF (tetrahydrofuran); Tris(tris(hydroxymethyl)aminomethane); μg (microgram(s)); μL(microliter(s)); μm (micrometer); μM (micromolar); wt % (weightpercent).

II. Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes, such as those inthe Schemes below.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediatesor products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups is described, e.g., in Kocienski, Protecting Groups,(Thieme, 2007); Robertson, Protecting Group Chemistry, (OxfordUniversity Press, 2000); Smith et al., March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, 6^(th) Ed. (Wiley,2007); Peturssion et al., “Protecting Groups in Carbohydrate Chemistry,”J. Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groupsin Organic Synthesis, 4th Ed., (Wiley, 2006).

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry, or by chromatographic methods such as high performanceliquid chromatography (HPLC) or thin layer chromatography (TLC).

The Schemes below provide general guidance in connection with preparingthe compounds of the invention. One skilled in the art would understandthat the preparations shown in the Schemes can be modified or optimizedusing general knowledge of organic chemistry to prepare variouscompounds of the invention.

Compounds of formula (I) can be prepared, e.g., using a process asillustrated in Scheme 1. In the process depicted in Scheme 1, a suitablearomatic amine of formula 1-1 is reacted with an acid of formula 1-2under conditions suitable for forming an amide bond to provide thecompound of formula (I). Suitable combinations for forming the amidebond include, e.g., the methods used to form amide bonds in peptides asdescribed, e.g., in Jones, Amino Acid and Peptide Synthesis, 2^(nd) Ed.,Oxford University Press, 2002; and Jones, The Chemical Synthesis ofPeptides (International Series of Monographs on Chemistry) (OxfordUniversity Press, 1994). An example of a suitable coupling agent isHATU/DIPEA.

Compounds of formula (I) can be prepared, e.g., using a process asillustrated in Scheme 2.

In the process depicted in Scheme 2, a suitable aromatic fused aromaticcompound of formula 2-1 can be oxidized to give an N-oxide 2-2. Examplesof suitable oxidizing agents include peracids such as mCPBA. The N-oxidegroup can then be used to direct functionalization of the 4-position ofthe N-oxide containing ring, e.g. by reaction with a suitableelectrophile or reaction with a suitable acid chloride or anhydridecompound, proceeding via initial nucleophilic reaction of the N-oxidewith the acid chloride or anhydride followed by nucleophilic addition tothe aromatic ring. An example of a suitable acid chloride or anhydrideis POCl₃ which can react with the N-oxide to introduce chlorine into the4-position. Thus, the N-oxide 2-2 can be reacted with POCl₃ to producethe 4-chloro-substituted compound 2-3. A 4-chloro substituent providesfunctionalization to enable the introduction of ring D into the compoundof formula (I) by suitable cross-coupling chemistry, e.g., nucleophilicsubstitution of the chlorine or suitable metal-catalyzed cross-couplingreactions. To introduce the amino group which forms the amide bond offormula (I), a nitro group can be introduced by electrophilic nitrationat the 3-position and then reduced to the required amine group. Thus,the chloro compound 2-4 can be reacted with a suitable nitrating agentto provide the aromatic nitro compound of formula 2-5. Examples ofsuitable nitrating agents include nitric acid. Since the nitro groupactivates the chloro at the 4-position to nucleophilic couplingreactions, it may be convenient to introduce ring D by reaction of the3-nitro-4-chloro compound, particularly when ring D is a heterocycleconnected via a nitrogen atom. Thus, reaction of compound 2-4 with asuitable precursor of ring D can provide a nitro compound of formula2-5. When ring D is a heterocycle connected via a nitrogen atom, thereaction can be carried out by nucleophilic substitution in the presenceof a suitable base, e.g. sodium hydride or sodium t-butoxide. Thereaction can also be carried out by suitable metal catalyzedcross-coupling reactions such as Buchwald-Hartwig cross-couplingchemistry. When ring D is not connected via nitrogen, other suitablecross-coupling reactions, e.g., Stille or Suzuki cross-couplingreactions. In other cases a suitable functional group such as nitrilecan be introduced and used as a precursor for synthesis of ring D.

The nitro group of compound 2-5 can be reduced to an amino group using asuitable reducing agent. Examples of suitable reducing agents includehydrogen gas, which can be reacted with the nitro compound in thepresence of a suitable catalyst, e.g., palladium, such as palladium inthe form of palladium on carbon. Suitable reducing agents also includemetals such as iron and zinc. Thus, reduction of nitro-compound 2-5provides an amino-compound 2-6, which can then be subjected toamide-bond coupling with a suitable acid of formula 2-7 to provide thecompound of formula (I).

Application of the general scheme described above to the preparation ofa compound of formula (I) wherein the compound of formula (I) contains adihydrocyclopentapyridine ring is illustrated in Scheme 3. As avariation of the scheme described above, instead of being nitrateddirectly, the chloropyridine compound 3-3 is transformed to amethoxypyridine 3-4 to take advantage of the superior efficacy of themethoxy group in activating the pyridine ring to electrophilicsubstitution and directing substitution to the 3-position.

Thus, in the process illustrated by Scheme 3, commercially availablecyclopentapyridine 3-1 can be oxidized with mCPBA to give correspondingN-oxide 3-2, which can be subsequently treated with POCl₃ to generatechloropyridine 3-3. Compound 3-3 can be transformed to methoxy compound3-4 by heating with sodium methoxide. The methoxypyridine 3-4 can thenbe nitrated with a suitable nitrating agent. Suitable conditions for thenitration include heating with potassium nitrate and sulfuric acid. Theresulting nitro compound 3-5 can be subjected to demethylation reactionto provide the hydroxypyridine 3-6. Suitable conditions fordemethylation include, e.g., heating with HBr. The hydroxypyridine 3-6can then be converted back to a chloropyridine 3-7 by reaction with asuitable acid chloride compound such as POCl₃. Then, as discussed above,the chloro compound 3-7 can be reacted to introduce ring D by a suitableprocedure which will depend on the nature of ring D, such as bynucleophilic substitution, or a cross-coupling reaction such asBuchwald-Hartwig, Stille or Suzuki cross-coupling reactions. Nitrocompound 3-8 can then be reduced to aminopyridine 3-9 through treatmentwith a suitable reducing agent such as hydrogen in the presence of acatalyst, e.g. Pd on carbon, or by reaction with iron in the presence ofammonium chloride. The resulting amino-pyridine can then be subjected toamide coupling with a carboxylic acid of formula 3-10 to provide anamide of formula 3-11, which corresponds to a compound of formula (I),wherein ring B is a fused cyclopentane ring.

A variation of the process shown in Scheme 3 to produce compoundswherein ring B is a functionalized cyclopentane ring can be carried outas shown in Scheme 4.

Thus, after coupling to introduce ring D, the compound 4-1(corresponding to compound 3-8 of Scheme 3) can be oxidized to anN-oxide 4-2 with a suitable oxidizing agent such as mCPBA.Functionalization of the cyclopentane ring is then achieved by reactionof the N-oxide 4-2 with a suitable electrophilic agent such as aceticanhydride, which initially acetylates the N-oxide which then undergoesrearrangement to provide the acetate compound 4-3. Then, in the samemanner as described above, the nitro compound is reduced to an aminocompound 4-4 using a suitable reducing agent such as hydrogen/Pd oncarbon or iron followed by amide coupling with a suitable acid offormula 4-5 to provide the amide of formula 4-6. The acetyl group ofcompound 4-6 can then be removed, e.g., by hydrolysis with a suitablebase, e.g., potassium carbonate or lithium hydroxide. The hydroxy groupof compound 4-7 can then be further transformed to other functionalgroups by methods known to one skilled in the art, and as illustrated inthe Examples.

A modification of the general scheme described above to the synthesis ofcompounds wherein ring B is a fused dihydrofuran ring is shown in Scheme5. In the process of Scheme 5, commercially available fluoroiodopyridine5-1 can be treated with LDA followed by ethylene sulfate to providecompound 5-2 via a rearrangement reaction (“halogen dance”). Compound5-2 can be hydrolyzed to alcohol 5-3 by treating with an acid, e.g.,HCl. Cyclization of alcohol 5-3 to a dihydrofuropyridine 5-4 can then beachieved by reaction under suitable basic conditions, e.g., heating withpotassium phosphate in dioxane. The dihydrofuropyridine compound 5-4 canthen be nitrated with a suitable nitrating agent such as nitric acid insulfuric acid to give the nitropyridine compound 5-5. The coupling ofcompound 5-5 to introduce ring D can then be achieved using the methodsdiscussed above, such as by nucleophilic substitution, or across-coupling reaction such as Buchwald-Hartwig, Stille or Suzukicross-coupling reactions. Then, analogously to the procedure describedabove, the resulting nitro compound 5-6 can be reduced to anaminopyridine 5-7 using a suitable reducing agent such as hydrogen/Pd oncarbon or iron followed by amide coupling with a suitable acid offormula 5-8 to provide the amide of formula 5-9, which corresponds to acompound of formula (I), wherein ring B is a fused dihydrofuran ring.

Further compounds of formula (I) can be synthesized as illustrated inScheme 6. Commercially available N-aminophthalimide 6-1 can be treatedwith 2,5-dimethoxy tetrahydrofuran at elevated temperature to provideisoindolinedione compound 6-2. When treated with hydrazine monohydrate,6-2 can be hydrolyzed to give 1-amino-pyrrole 6-3. The aminopyrrole 6-3can be transformed to 6-4 through condensation withdiethyl-2-(ethoxymethylene)malonate and removal of ethanol generated.Compound 6-4 can be cyclized in a high boiling solvent such as DowthermA under elevated temperature to generate the pyrrolopyridazine compound6-5. Compound 6-5 can be reacted with POCl₃ to afford the correspondingchloropyrrolopyridazine 6-6. Coupling of 6-6 with an appropriate ring Dcompounds can be achieved with methods known to one skilled in the art,such as direct coupling or Buchwald-Hartwig coupling when ring D isattached to pyrrolopyridazine through nitrogen; or Suzuki coupling whenring D is attached to pyrrolopyridazine through carbon. Saponificationof the ester group of compound 6-7 to provide a carboxylic acid 6-8,followed by Curtius rearrangement to give a Boc-protected amino compound6-9 and, deprotection of the Boc group can then give aminopyrrolopyridazines 6-10. Finally, amide coupling of 6-10 with a suitablering A acid can yield desired compounds of formula 6-11. Thesubstitutions on 6-11 can be further transformed to desired functionalgroups in the final product, or in any of the steps of the synthesis,using methods know to one skilled in the art.

For the synthesis of particular compounds, the general schemes describedabove can be modified. For example, the products or intermediates can bemodified to introduce particular functional groups. Alternatively, thesubstituents can be modified at any step of the overall synthesis bymethods know to one skilled in the art, e.g., as described by Larock,Comprehensive Organic Transformations: A Guide to Functional GroupPreparations (Wiley, 1999); and Katritzky et al. (Ed.), ComprehensiveOrganic Functional Group Transformations (Pergamon Press 1996).

Starting materials, reagents and intermediates whose synthesis is notdescribed herein are either commercially available, known in theliterature, or may be prepared by methods known to one skilled in theart.

It will be appreciated by one skilled in the art that the processesdescribed are not the exclusive means by which compounds of theinvention may be synthesized and that a broad repertoire of syntheticorganic reactions is available to be potentially employed insynthesizing compounds of the invention. The person skilled in the artknows how to select and implement appropriate synthetic routes. Suitablesynthetic methods of starting materials, intermediates and products maybe identified by reference to the literature, including referencesources such as: Advances in Heterocyclic Chemistry, Vols. 1-107(Elsevier, 1963-2012); Journal of Heterocyclic Chemistry Vols. 1-49(Journal of Heterocyclic Chemistry, 1964-2012); Carreira, et al. (Ed.)Science of Synthesis, Vols. 1-48 (2001-2010) and Knowledge UpdatesKU2010/1-4; 2011/1-4; 2012/1-2 (Thieme, 2001-2012); Katritzky, et al.(Ed.) Comprehensive Organic Functional Group Transformations, (PergamonPress, 1996); Katritzky et al. (Ed.); Comprehensive Organic FunctionalGroup Transformations II (Elsevier, 2^(nd) Edition, 2004); Katritzky etal. (Ed.), Comprehensive Heterocyclic Chemistry (Pergamon Press, 1984);Katritzky et al., Comprehensive Heterocyclic Chemistry II, (PergamonPress, 1996); Smith et al., March's Advanced Organic Chemistry:Reactions, Mechanisms, and Structure, 6^(th) Ed. (Wiley, 2007); Trost etal. (Ed.), Comprehensive Organic Synthesis (Pergamon Press, 1991).

III. Uses of the Compounds

Compounds of the invention can inhibit the activity of one or moremembers of the Pim kinase family and, thus, are useful in treatingdiseases and disorders associated with activity of Pim kinases. For theuses described herein, any of the compounds of the invention, includingany of the embodiments thereof, may be used.

The compounds of the invention can inhibit one or more of Pim1, Pim2 andPim3. In some embodiments the compounds are selective for one Pim kinaseover another. “Selective” in this context means that the compound bindsto or inhibits a Pim kinase with greater affinity or potency,respectively, compared to a reference enzyme, such as another Pimkinase. For example, the compounds can be selective for Pim1 over Pim2and Pim3, selective for Pim2 over Pim1 and Pim3, or selective for Pim3over Pim1 and Pim2. In some embodiments, the compounds inhibit all ofthe Pim family members (e.g., Pim1, Pim2 and Pim3). In some embodiments,the compounds can be selective for Pim over other kinases such asreceptor and non-receptor Ser/Thr kinases such as Akt1, Akt2, Akt3,TGF-βR, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPKand mTOR; receptor Tyr kinases such as EGFR, HER2, HER3, HER4, INS-R,IGF-1R, IR-R, PDGFαR, PDGFβR, CSFIR, KIT, FLK-II, KDR/FLK-1, FLK-4,fit-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC,FLT3, VEGFR/Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2; andnon-receptor Tyr kinases such as Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK,JAK or ABL. In general, selectivity can be at least about 5-fold, atleast about 10-fold, at least about 20-fold, at least about 50-fold, atleast about 100-fold, at least about 200-fold, at least about 500-foldor at least about 1000-fold. The method of inhibiting a Pim1, Pim2 orPim3 kinase includes contacting the appropriate enzyme with the compoundof formula (I), or any of the embodiments thereof, or a pharmaceuticallyacceptable salt thereof.

Thus, the present disclosure provides methods of treating a Pimkinase-associated disease or disorder in an individual (e.g., patient)by administering to the individual in need of such treatment atherapeutically effective amount or dose of a compound of formula (I),or any of the embodiments thereof, or a pharmaceutical compositionthereof. The present disclosure also provides a compound of formula (I),or any of the embodiments thereof, or a pharmaceutical compositionthereof, for use in treating a Pim kinase-associated disease ordisorder. Also provided is the use of a compound of formula (I), or anyof the embodiments thereof, or a pharmaceutical composition thereof, inthe manufacture of a medicament for treating a Pim kinase-associateddisease or disorder.

A Pim kinase-associated disease can include any disease, disorder orcondition that is directly or indirectly linked to expression oractivity of the Pim kinase, including over-expression and/or abnormalactivity levels. Abnormal activity levels can be determined by comparingactivity level in normal, healthy tissue or cells with activity level indiseased cells. A Pim kinase-associated disease can also include anydisease, disorder or condition that can be prevented, ameliorated,inhibited or cured by modulating Pim kinase activity. In someembodiments, the disease is characterized by the abnormal activity orexpression (e.g., overexpression) of one or more Pim1, Pim2 and Pim3. Insome embodiments, the disease is characterized by mutant Pim1, Pim2 orPim3. A Pim kinase associated disease can also refer to any disease,disorder or condition wherein modulating the expression or activity ofone or more Pim kinases is beneficial.

Pim kinase associated diseases that can be treated using the compoundsof the invention include cancer, including, in particular, cancers inwhich Pim kinases are upregulated or an oncogene, e.g., Myc or BCL2, isactivated. Pim kinase associated diseases include solid tumors, e.g.,prostate cancer, colon cancer, esophageal cancer, endometrial cancer,ovarian cancer, uterine cancer, renal cancer, hepatic cancer, pancreaticcancer, gastric cancer, breast cancer, lung cancer, cancers of the heador neck, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc. Pimkinase associated diseases also include hematological cancers, e.g.,lymphoma, leukemia such as acute lymphoblastic leukemia (ALL), acutemyelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronicmyelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL),mantle cell lymphoma, non-Hodgkin lymphoma (including relapsednon-Hodgkin lymphoma, refractory non-Hodgkin lymphoma and recurrentfollicular non-Hodgkin lymphoma), Hodgkin lymphoma and multiple myeloma.

Pim kinase associated diseases that can be treated using the compoundsof the invention also include myeloproliferative disorders such aspolycythemia vera (PV), essential thrombocythemia (ET), chronicmyelogenous leukemia (CML) and the like. The myeloproliferative disordercan be myelofibrosis such as primary myelofibrosis (PMF), myelofibrosiswith myeloid metaplasia (MMM), post-polycythemia vera/essentialthrombocythemia myelofibrosis (Post-PV/ET MF), post-essentialthrombocythemia myelofibrosis (Post-ET MF) or post-polycythemia veramyelofibrosis (Post-PV MF).

Pim kinase-associated diseases that can be treated with compoundsaccording to the invention also include immune disorders such asautoimmune diseases. The immune disorders include multiple sclerosis,rheumatoid arthritis, allergy, food allergy, asthma, lupus, inflammatorybowel disease and ulcerative colitis.

Pim kinase-associated diseases that can be treated with compoundsaccording to the invention also include atherosclerosis.

The compounds of the invention can also be used to inhibit diseaseprocesses in which Pim-kinases are involved, including angiogenesis andtumor metastasis.

Due to the fact that Pim kinases are regulated by the JAK/STAT pathway,the compounds of the invention are useful to treat diseases in whichmodulating JAK/STAT signaling is beneficial. Thus, other diseases thatcan be treated using the compounds of the invention include Crohn'sdisease, irritable bowel syndrome, pancreatitis, diverticulosis, Grave'sdisease, juvenile rheumatoid arthritis, osteoarthritis, psoriaticarthritis, ankylosing spondylitis, myasthenia gravis, vasculitis,autoimmune thyroiditis, dermatitis, psoriasis, scleroderma, systemicsclerosis, vitiligo, graft versus host disease, Sjogren's syndrome,glomerulonephritis and diabetes mellitis (type I).

It is believed that compounds of Formula (I), or any of the embodimentsthereof, may possess satisfactory pharmacological profile and promisingbiopharmaceutical properties, such as toxicological profile, metabolismand pharmacokinetic properties, solubility, and permeability. It will beunderstood that determination of appropriate biopharmaceuticalproperties is within the knowledge of a person skilled in the art, e.g.,determination of cytotoxicity in HEK-293 cells or inhibition of the hERGpotassium ion channel to determine potential toxicity.

The terms “individual” or “patient,” used interchangeably, refer to anyanimal, including mammals, preferably mice, rats, other rodents,rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and mostpreferably humans.

The phrase “therapeutically effective amount” refers to the amount ofactive compound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal, individual or human thatis being sought by a researcher, veterinarian, medical doctor or otherclinician.

The term “treating” or “treatment” refers to one or more of (1)inhibiting the disease; e.g., inhibiting a disease, condition ordisorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology);and (2) ameliorating the disease; e.g., ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing the pathology and/or symptomatology) such as decreasingthe severity of disease. In one embodiment, treating or treatmentincludes preventing or reducing the risk of developing the disease;e.g., preventing or reducing the risk of developing a disease, conditionor disorder in an individual who may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease.

Combination Therapies

Cancer cell growth and survival can be impacted by multiple signalingpathways. Thus, it is useful to combine different kinase inhibitors,exhibiting different preferences in the kinases which they modulate theactivities of, to treat such conditions. Targeting more than onesignaling pathway (or more than one biological molecule involved in agiven signaling pathway) may reduce the likelihood of drug-resistancearising in a cell population, and/or reduce the toxicity of treatment.

Accordingly, the Pim inhibitors of the present invention can be used incombination with one or more other kinase inhibitors for the treatmentof diseases, such as cancer, that are impacted by multiple signalingpathways. For example, the compounds of the invention can be combinedwith one or more inhibitors of the following kinases for the treatmentof cancer: Akt1, Akt2, Akt3, TGF-βR, PKA, PKG, PKC, CaM-kinase,phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4,INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR, CSFIR, KIT, FLK-II, KDR/FLK-1,FLK-4, fit-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB,TRKC, FLT3, VEGFR/Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2,Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK and B-Raf.Additionally, the Pim inhibitors of the invention can be combined withinhibitors of kinases associated with the PIK3/Akt/mTOR signalingpathway, such as PI3K, Akt (including Akt1, Akt2 and Akt3) and mTORkinases.

The Pim inhibitors of the present invention can further be used incombination with other methods of treating cancers, for example bychemotherapy, irradiation, or surgery. The compounds can be administeredin combination with one or more anti-cancer drugs, such as achemotherapeutics. Example chemotherapeutics include any of: abarelix,aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine,anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab,bexarotene, bleomycin, bortezombi, bortezomib, busulfan intravenous,busulfan oral, calusterone, capecitabine, carboplatin, carmustine,cetuximab, chlorambucil, cisplatin, cladribine, clofarabine,cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparinsodium, dasatinib, daunorubicin, decitabine, denileukin, denileukindiftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolonepropionate, eculizumab, epirubicin, erlotinib, estramustine, etoposidephosphate, etoposide, exemestane, fentanyl citrate, filgrastim,floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib,gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelinacetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinibmesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate,lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole,lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine,methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone,nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin,paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine,quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib,streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide,teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan,toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard,valrubicin, vinblastine, vincristine, vinorelbine, vorinostat andzoledronate.

The Pim inhibitors of the present invention can further be used incombination with one or more anti-inflammatory agents, steroids,immunosuppressants, or therapeutic anti-bodies.

When more than one pharmaceutical agent is administered to a patient,they can be administered simultaneously, sequentially, or in combination(e.g., for more than two agents).

IV. Formulation, Dosage Forms and Administration

When employed as pharmaceuticals, the compounds of the invention can beadministered in the form of pharmaceutical compositions. Thus thepresent disclosure provides a composition comprising a compound offormula (I), or a pharmaceutically acceptable salt thereof, or any ofthe embodiments thereof, and at least one pharmaceutically acceptablecarrier. These compositions can be prepared in a manner well known inthe pharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is indicated and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be,e.g., by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the invention or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers (excipients). In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the invention, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, e.g., a capsule, sachet, paper, orother container. When the excipient serves as a diluent, it can be asolid, semi-solid, or liquid material, which acts as a vehicle, carrieror medium for the active ingredient. Thus, the compositions can be inthe form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, e.g., up to 10% by weightof the active compound, soft and hard gelatin capsules, suppositories,sterile injectable solutions and sterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g., about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art see, e.g., WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; and sweetening agents and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

In some embodiments, the pharmaceutical composition comprises silicifiedmicrocrystalline cellulose (SMCC) and at least one compound describedherein, or a pharmaceutically acceptable salt thereof. In someembodiments, the silicified microcrystalline cellulose comprises about98% microcrystalline cellulose and about 2% silicon dioxide w/w.

In some embodiments, the composition is a sustained release compositioncomprising at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier. In some embodiments, the composition comprises at least onecompound described herein, or a pharmaceutically acceptable saltthereof, and at least one component selected from microcrystallinecellulose, lactose monohydrate, hydroxypropyl methylcellulose andpolyethylene oxide. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and microcrystalline cellulose, lactose monohydrate andhydroxypropyl methylcellulose. In some embodiments, the compositioncomprises at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and microcrystalline cellulose, lactosemonohydrate and polyethylene oxide. In some embodiments, the compositionfurther comprises magnesium stearate or silicon dioxide. In someembodiments, the microcrystalline cellulose is Avicel PH102™. In someembodiments, the lactose monohydrate is Fast-flo 316™. In someembodiments, the hydroxypropyl methylcellulose is hydroxypropylmethylcellulose 2208 K4M (e.g., Methocel K4 M Premier™) and/orhydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel K00LV™). Insome embodiments, the polyethylene oxide is polyethylene oxide WSR 1105(e.g., Polyox WSR 1105™).

In some embodiments, a wet granulation process is used to produce thecomposition. In some embodiments, a dry granulation process is used toproduce the composition.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1,000 mg (1 g), more usually about 100mg to about 500 mg, of the active ingredient. In some embodiments, eachdosage contains about 10 mg of the active ingredient. In someembodiments, each dosage contains about 50 mg of the active ingredient.In some embodiments, each dosage contains about 25 mg of the activeingredient. The term “unit dosage forms” refers to physically discreteunits suitable as unitary dosages for human subjects and other mammals,each unit containing a predetermined quantity of active materialcalculated to produce the desired therapeutic effect, in associationwith a suitable pharmaceutical excipient.

The components used to formulate the pharmaceutical compositions are ofhigh purity and are substantially free of potentially harmfulcontaminants (e.g., at least National Food grade, generally at leastanalytical grade, and more typically at least pharmaceutical grade).Particularly for human consumption, the composition is preferablymanufactured or formulated under Good Manufacturing Practice standardsas defined in the applicable regulations of the U.S. Food and DrugAdministration. For example, suitable formulations may be sterile and/orsubstantially isotonic and/or in full compliance with all GoodManufacturing Practice regulations of the U.S. Food and DrugAdministration.

The active compound may be effective over a wide dosage range and isgenerally administered in a therapeutically effective amount. It will beunderstood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight and response of the individual patient, the severity of thepatient's symptoms and the like.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, e.g., about 0.1 to about 1000 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face mask, tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, e.g., liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline®(petroleum jelly) and the like. Carrier compositions of creams can bebased on water in combination with glycerol and one or more othercomponents, e.g., glycerinemonostearate, PEG-glycerinemonostearate andcetylstearyl alcohol. Gels can be formulated using isopropyl alcohol andwater, suitably in combination with other components such as, e.g.,glycerol, hydroxyethyl cellulose and the like. In some embodiments,topical formulations contain at least about 0.1, at least about 0.25, atleast about 0.5, at least about 1, at least about 2, or at least about 5wt % of the compound of the invention. The topical formulations can besuitably packaged in tubes of, e.g., 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers or stabilizers will resultin the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

V. Labeled Compounds and Assay Methods

The compounds of the invention can further be useful in investigationsof biological processes, including kinase signaling, in normal andabnormal tissues. Thus, another aspect of the present invention relatesto labeled compounds of the invention (radio-labeled,fluorescent-labeled, etc.) that would be useful not only in imagingtechniques but also in assays, both in vitro and in vivo, for localizingand quantitating Pim kinases in tissue samples, including human, and foridentifying Pim kinase ligands by inhibition binding of a labeledcompound. Accordingly, the present invention includes Pim kinase assaysthat contain such labeled compounds.

The present invention further includes isotopically-labeled compounds ofthe invention. An “isotopically” or “radio-labeled” compound is acompound of the invention where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present invention include but are not limited to ³H(also written as T for tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O,¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. Theradionuclide that is incorporated in the instant radio-labeled compoundswill depend on the specific application of that radio-labeled compound.For example, for in vitro Pim kinase labeling and competition assays,compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I, ³⁵S or willgenerally be most useful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I,¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br will generally be most useful.

It is to be understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br. In some embodiments, the compoundincorporates 1, 2 or 3 deuterium atoms. Synthetic methods forincorporating radio-isotopes into organic compounds are known in theart.

Specifically, a labeled compound of the invention can be used in ascreening assay to identify and/or evaluate compounds. For example, anewly synthesized or identified compound (i.e., test compound) which islabeled can be evaluated for its ability to bind a Pim-kinase bymonitoring its concentration variation when contacting with the Pimkinase, through tracking of the labeling. For example, a test compound(labeled) can be evaluated for its ability to reduce binding of anothercompound which is known to bind to a Pim kinase (i.e., standardcompound). Accordingly, the ability of a test compound to compete withthe standard compound for binding to the Pim kinase directly correlatesto its binding affinity. Conversely, in some other screening assays, thestandard compound is labeled and test compounds are unlabeled.Accordingly, the concentration of the labeled standard compound ismonitored in order to evaluate the competition between the standardcompound and the test compound, and the relative binding affinity of thetest compound is thus ascertained.

VI. Kits

The present disclosure also includes pharmaceutical kits useful, e.g.,in the treatment or prevention of Pim kinase-associated diseases ordisorders, such as cancer, which include one or more containerscontaining a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of formula (I), or any of the embodimentsthereof. Such kits can further include one or more of variousconventional pharmaceutical kit components, such as, e.g., containerswith one or more pharmaceutically acceptable carriers, additionalcontainers, etc., as will be readily apparent to those skilled in theart. Instructions, either as inserts or as labels, indicating quantitiesof the components to be administered, guidelines for administration,and/or guidelines for mixing the components, can also be included in thekit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples have been found to bePim-kinase inhibitors according to at least one assay described herein.

EXAMPLES

Experimental procedures for compounds of the invention are providedbelow. Open Access Preparative LC-MS Purification of some of thecompounds prepared was performed on Waters mass directed fractionationsystems. The basic equipment setup, protocols, and control software forthe operation of these systems have been described in detail inliterature. See, e.g., Blom, “Two-Pump At Column Dilution Configurationfor Preparative LC-MS”, K. Blom, J. Combi. Chem., 2002, 4, 295-301; Blomet al., “Optimizing Preparative LC-MS Configurations and Methods forParallel Synthesis Purification”, J. Combi. Chem., 2003, 5, 670-83; andBlom et al., “Preparative LC-MS Purification: Improved Compound SpecificMethod Optimization”, J. Combi. Chem., 2004, 6, 874-883.

In the cases where diastereoisomers were isolated, the HPLC retentiontimes were obtained from analytical LCMS (Waters SunFire™ column, 2.1mm×50 mm, 5 μm particle size, eluting with a gradient of MeOH/watercontaining 0.025% TFA).

Example 15-Amino-N-{4-[(3S)-3-aminopiperidin-1-yl]quinolin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

Step 1. tert-Butyl[(3S)-1-(3-nitroquinolin-4-yl)piperidin-3-yl]carbamate

To a 5 mL microwave vial containing 4-chloro-3-nitroquinoline (ArkPharm, 312.9 mg, 1.500 mmol) and tert-butyl (3S)-piperidin-3-ylcarbamate(Combi-Blocks, 358.9 mg, 1.792 mmol), 1-butanol (3.00 mL) was addedfollowed by DIPEA (405.1 mg, 3.134 mmol). The reaction mixture washeated at 100° C. under microwave irradiation for 2 h. The reaction wasthen concentrated under reduced pressure. The resulting residue waspurified by chromatography on silica gel (0-100% EtOAc in hexanes) togive the sub-title compound as a yellow oil (293.5 mg, 53%). LCMS calc.for C₁₉H₂₅N₄O₄ (M+H)⁺: m/z=373.2; found 373.2.

Step 2. tert-Butyl[(3S)-1-(3-aminoquinolin-4-yl)piperidin-3-yl]carbamate

EtOH (5.00 mL) followed by water (1.00 mL) were added to a vialcontaining tert-butyl[(3S)-1-(3-nitroquinolin-4-yl)piperidin-3-yl]carbamate (118.9 mg, 0.3193mmol), iron powder (199.0 mg, 3.563 mmol) and NH₄Cl (288.9 mg, 5.401mmol). The mixture was stirred at 80° C. for 1 h. The reaction mixturewas filtered through a pad of diatomaceous earth. The pad was elutedwith a 10% aq. K₃PO₄ (20 mL), and EtOAc (20 mL). The organic layer waswashed with brine (20 mL), dried over Na₂SO₄, and concentrated underreduced pressure. The resulting residue was purified by chromatographyon silica gel (0-100% EtOAc in hexanes) to give the sub-title compoundas a pale yellow solid (36.9 mg, 34%). LCMS calc. for C₁₉H₂₇N₄O₂ (M+H)⁺:m/z=343.2; found 343.2.

Step 3. Methyl 5-amino-2-bromo-1,3-thiazole-4-carboxylate

To a solution of methyl 5-amino-1,3-thiazole-4-carboxylate (J & WPharmLab, 10.0 g, 63.2 mmol) in THF (100 mL), N-bromosuccinimide (12.0g, 67.4 mmol) was added portion-wise. After stirring at room temperaturefor 1 h, the mixture reaction was filtered to give a first crop ofproduct as a pink solid (9.8 g). The filtrate was concentrated underreduced pressure. The resulting residue was triturated with EtOAc (15mL) and filtered to give a second crop of product as a pink solid (5.0g, total yield: 99%). LCMS calc. for C₅H₆BrN₂O₂S (M+H)⁺: m/z=236.9;found 237.0.

Step 4. Methyl2-bromo-5-[(tert-butoxycarbonyl)amino]-1,3-thiazole-4-carboxylate

To a solution of methyl 5-amino-2-bromo-1,3-thiazole-4-carboxylate (14.8g, 62.4 mmol) in THF (100 mL), di-tert-butyl dicarbonate (18.0 g, 82.2mmol), DMAP (1.5 g, 13 mmol) and triethylamine (17.6 mL, 126 mmol) wereadded. After stirring at room temperature for 16 h, the reaction mixturewas diluted with EtOAc (400 mL) and washed with water (2×250 mL). Theorganic layer was washed with brine (250 mL), dried over Na₂SO₄, andconcentrated under reduced pressure. The resulting residue was purifiedby chromatography on silica gel (0-50% EtOAc in hexanes) to give thesub-title compound as a white solid (15.1 g, 72%). LCMS calc. forC₁₀H₁₄BrN₂O₄S (M+H)⁺: m/z=337.0; found 337.0.

Step 5. Methyl5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylate

To a round bottle flask equipped with a magnetic stir bar, methyl2-bromo-5-[(tert-butoxycarbonyl)amino]-1,3-thiazole-4-carboxylate (9.60g, 28.5 mmol) was added, followed by2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Combi-Blocks, 8.88 g, 37.0 mmol) andbis(tri-tert-butylphosphine)palladium (2.30 g, 4.50 mmol). The flask wassealed with a rubber septum, and evacuated and backfilled with nitrogenthree times. 1,4-Dioxane (40.0 mL) was added via a syringe, followed byDIPEA (9.6 mL, 55 mmol) and deoxygenated water (2.0 mL). The resultingmixture was heated at 100° C. for 1 h. After cooling to roomtemperature, the mixture was diluted with EtOAc (200 mL) and washed withwater (100 mL) and brine (200 mL), then dried over Na₂SO₄, andconcentrated under reduced pressure. The resulting residue was purifiedby chromatography on silica gel (0-100% EtOAc in hexanes) to give thesub-title compound as a white solid (9.80 g, 93%). LCMS calc. forC₁₆H₁₇F₂N₂O₄S (M+H)⁺: m/z=371.1; found 371.0.

Step 6.5-[(tert-Butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylicAcid

To a suspension of methyl5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylate(6.99 g, 18.9 mmol) in MeOH (50.0 mL), lithium hydroxide monohydrate(5.24 g, 125 mmol) was added, followed by water (50.0 mL). The mixturewas heated at 60° C. for 5 h. The reaction mixture was then cooled to 0°C., and 6 M HCl was added slowly until the pH reached 2. The resultingsolid was collected by filtration and the filter cake was washed withwater (50 mL) and MeOH/water (1:1, 50 mL) to provide the sub-titlecompound as a yellow solid (6.59 g, 98%). LCMS calc. for C₁₅H₁₅F₂N₂O₄S(M+H)⁺: m/z=357.1; found 357.0.

Step 7. tert-Butyl{(3S)-1-[3-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)quinolin-4-yl]piperidin-3-yl}carbamate

To a solution of5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylicacid (81.1 mg, 0.228 mmol) in THF (0.5 mL), a solution of1-chloro-N,N,2-trimethylpropenylamine (Aldrich, 80.5 mg, 0.602 mmol) inTHF (1.0 mL) was added. The mixture was stirred at room temperature for5 h. To the above mixture was added a solution of tert-butyl[(3S)-1-(3-aminoquinolin-4-yl)piperidin-3-yl]carbamate (63.8 mg, 0.186mmol) in THF (2.0 mL) followed by pyridine (146.4 mg, 1.851 mmol). Themixture was stirred at room temperature for 2 h, and then concentratedunder reduced pressure. The resulting residue was purified bychromatography on silica gel (0-100% EtOAc in hexanes) to afford thesub-title compound as a yellow solid (115.8 mg, 91%). LCMS calc. forC₃₄H₃₉F₂N₆O₅S (M+H)⁺: m/z=681.3; found 681.3.

Step 8.5-Amino-N-{4-[(3S)-3-aminopiperidin-1-yl]quinolin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

To a solution of tert-butyl{(3S)-1-[3-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)quinolin-4-yl]piperidin-3-yl}carbamate(115.8 mg, 0.17 mmol) in DCM (2.0 mL) was added TFA (2.0 mL). Themixture was stirred at room temperature for 30 min., and thenconcentrated under reduced pressure. The resulting residue was purifiedusing RP-HPLC (XBridge™ C18 column, eluting with a gradient ofMeCN/water containing 0.15% NH₄OH, at flow rate of 30 mL/min.) to affordthe title compound as a white solid (20.5 mg, 25%). LCMS calc. forC₂₄H₂₃F₂N₆OS (M+H)⁺: m/z=481.2; found 481.2.

Example 2N-{4-[(3S)-3-Aminopiperidin-1-yl]quinolin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

Step 1. Ethyl 2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylate

To a screw-cap vial equipped with a magnetic stir bar, ethyl2-bromo-1,3-thiazole-4-carboxylate (Ark Pharm, 2.026 g, 8.582 mmol) wasadded followed by2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Combi-Blocks, 2.47 g, 10.3 mmol) andbis(tri-tert-butylphosphine)palladium (781.8 mg, 1.530 mmol). The vialwas sealed with a PTFE-lined septum, and was then evacuated andbackfilled with nitrogen three times. 1,4-Dioxane (10.0 mL) was addedvia syringe, followed by DIPEA (2.41 g, 18.6 mmol) and deoxygenatedwater (0.60 mL). The reaction mixture was stirred at 120° C. for 3 h.After cooling to room temperature, the mixture was filtered through asilica gel plug (eluted with EtOAc). The filtrate was concentrated underreduced pressure, and the residue was purified by chromatography onsilica gel (0-100% EtOAc in hexanes) to give the title compound as apale yellow oil (1.739 g, 75%). LCMS calc. for C₁₂H₁₀F₂NO₂S (M+H)⁺:m/z=270.0; found 270.0.

Step 2. 2-(2,6-Difluorophenyl)-1,3-thiazole-4-carboxylic Acid

To a solution of ethyl 2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylate(1.72 g, 6.39 mmol) in THF (40.0 mL), lithium hydroxide monohydrate(1.51 g, 36.0 mmol) was added followed by water (10.0 mL). The mixturewas stirred at 60° C. for 5 h. The reaction mixture was then cooled to0° C., and 6 M HCl was added slowly until the pH reached 2. The mixturewas diluted with EtOAc (250 mL), washed with brine (200 mL), dried overNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby chromatography on silica gel (0-30% MeOH in DCM) to give the titlecompound as a white solid (1.49 g, 97%). LCMS calc. for C10H₆F₂NO₂S(M+H)⁺: m/z=242.0; found 242.0.

Step 3. tert-Butyl{(3S)-1-[3-({[2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)quinolin-4-yl]piperidin-3-yl}carbamate

To a suspension of 2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid(28.5 mg, 0.118 mmol) in DCM (0.5 mL), a solution of1-chloro-N,N,2-trimethylpropenylamine (45.0 mg, 0.337 mmol) in DCM (1.0mL) was added slowly. The mixture was stirred at room temperature for 2h. A solution of tert-butyl[(3S)-1-(3-aminoquinolin-4-yl)piperidin-3-yl]carbamate (from step 2 inExample 1, 36.9 mg, 0.108 mmol) in DCM (2.0 mL) was added, followed bypyridine (93.2 mg, 1.18 mmol). The mixture was then stirred at roomtemperature for a further 2 h, and then concentrated under reducedpressure. The resulting residue was purified by chromatography on silicagel (0-100% EtOAc in hexanes) to give the title compound as a paleyellow oil (57.4 mg, 94%). LCMS calc. for C₂₉H₃₀F₂N₅O₃S (M+H)⁺:m/z=566.2; found 566.2.

Step 4.N-{4-[(3S)-3-Aminopiperidin-1-yl]quinolin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

TFA (2.0 mL) was added to a solution of tert-butyl{(3S)-1-[3-({[2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)quinolin-4-yl]piperidin-3-yl}carbamate(57.4 mg, 0.101 mmol) in DCM (2.0 mL). The mixture was stirred at roomtemperature for 30 min., and then concentrated under reduced pressure.The resulting residue was purified using RP-HPLC (XBridge™ C18 column,eluting with a gradient of MeCN/water containing 0.15% NH₄OH, at flowrate of 30 mL/min.) to afford the title compound as a white solid (25.4mg, 54%). LCMS calc. for C₂₄H₂₂F₂N₅OS (M+H)⁺: m/z=466.1; found 466.2.

Example 35-Amino-N-{4-[(3S)-3-aminopiperidin-1-yl]thieno[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

Step 1. 5-Nitrothieno[2,3-b]pyridin-4-ol

To a solution of thieno[2,3-b]pyridin-4-ol (J & W PharmLab, 1.015 g,6.714 mmol) in DCM (15 mL) at −10° C., a solution ofN,N,N-tributylbutan-1-aminium nitrate (3.125 g, 10.26 mmol) in DCM (20mL) was added. Trifluoroacetic anhydride (2.334 g, 11.11 mmol) was addeddropwise. After stirring at −10° C. for 30 min., the mixture was allowedto warm to room temperature and stirred for 24 h. The reaction mixturewas concentrated under reduced pressure. The resulting residue wastriturated with ether (50 mL), and filtered. The filter cake was washedwith water (100 mL) and ether/MeOH (1:1, 80 mL), and then dried to givethe sub-title compound as a yellow solid (937.2 mg, 71%). LCMS calc. forC₇H₅N₂O₃S (M+H)⁺: m/z=197.0; found 197.0.

Step 2. 4-Chloro-5-nitrothieno[2,3-b]pyridine

To 5-nitrothieno[2,3-b]pyridin-4-ol (607.9 mg, 3.099 mmol), POCl₃ (6.00mL) was added, then the mixture was stirred at 110° C. for 1 h. Thereaction mixture was then concentrated under reduced pressure. Theresulting residue was dissolved in DCM (50 mL), and a saturated aq.NaHCO₃ (50 mL) was added slowly. The organic layer was washed with water(50 mL) and brine (50 mL), then dried over Na₂SO₄ and concentrated underreduced pressure. The residue was purified by chromatography on silicagel (0 to 50% EtOAc in hexanes) to afford the sub-title compound as apale yellow solid (605.3 mg, 91%). LCMS calc. for C₇H₄ClN₂O₂S (M+H)⁺:m/z=215.0; found 215.0.

Step 3. tert-Butyl[(3S)-1-(5-nitrothieno[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate

To a vial containing 4-chloro-5-nitrothieno[2,3-b]pyridine (138.2 mg,0.6439 mmol) and tert-butyl (3S)-piperidin-3-ylcarbamate (Combi-Blocks,325.5 mg, 1.625 mmol), 1-butanol (3.00 mL) was added, followed by DIPEA(201.4 mg, 1.558 mmol), then the mixture was stirred at 110° C. for 12h. After cooling to room temperature, the reaction mixture wasconcentrated under reduced pressure. The resulting residue was purifiedby chromatography on silica gel (0-100% EtOAc in hexanes) to give thetitle compound as a yellow solid (228.4 mg, 94%). LCMS calc. forC₁₇H₂₃N₄O₄S (M+H)⁺: m/z=379.1; found 379.2.

Step 4. tert-Butyl[(3S)-1-(5-aminothieno[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate

To a vial containing tert-butyl[(3S)-1-(5-nitrothieno[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate(228.4 mg, 0.6035 mmol), iron powder (357.7 mg, 6.405 mmol) and NH₄Cl(567.8 mg, 10.61 mmol), EtOH (5.00 mL) was added, followed by water(1.00 mL). The mixture was stirred at 80° C. for 1 h. The reactionmixture was then filtered through a pad of diatomaceous earth. Thediatomaceous earth pad was eluted with a 10% aq. K₃PO₄ (30 mL), andEtOAc (30 mL). The organic layer was washed with brine (30 mL), thendried over Na₂SO₄, and concentrated under reduced pressure. Theresulting residue (212.9 mg) was used in the next step without furtherpurification. LCMS calc. for C₁₇H₂₅N₄O₂S (M+H)⁺: m/z=349.2; found 349.2.

Step 5. tert-Butyl{(3S)-1-[5-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)thieno[2,3-b]pyridin-4-yl]piperidin-3-yl}carbamate

To a solution of5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylicacid (Example 1, step 6, 176.4 mg, 0.4950 mmol) in THF (0.5 mL), asolution of 1-chloro-N,N,2-trimethylpropenylamine (169.8 mg, 1.271 mmol)in THF (1.0 mL) was added slowly. The mixture was stirred at roomtemperature for 5 h. A solution of tert-butyl[(3S)-1-(5-aminothieno[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate(139.6 mg, 0.4006 mmol) in THF (2.0 mL) was then added to the resultingmixture, followed by pyridine (316.1 mg, 3.996 mmol), and the mixturewas stirred at room temperature for a further 2 h. The mixture was thenconcentrated under reduced pressure and the resulting residue waspurified by chromatography on silica gel (0-100% EtOAc in hexanes) toafford the sub-title compound as a dark semi-solid (230.7 mg, 84%). LCMScalc. for C₃₂H₃₇F₂N₆O₅S₂ (M+H)⁺: m/z=687.2; found 687.2.

Step 6.5-Amino-N-{4-[(3S)-3-aminopiperidin-1-yl]thieno[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

TFA (2.0 mL) was added to a solution of tert-butyl{(3S)-1-[5-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)thieno[2,3-b]pyridin-4-yl]piperidin-3-yl}carbamate(230.7 mg, 0.3359 mmol) in DCM (2.0 mL). The mixture was stirred at roomtemperature for 30 min., and then concentrated under reduced pressure.The resulting residue was purified using RP-HPLC (XBridge™ C18 column,eluting with a gradient of MeCN/water containing 0.1% NH₄OH, at flowrate of 30 mL/min.) to afford the title compound as a white solid (55.3mg, 34%). LCMS calc. for C₂₂H₂₁F₂N₆OS₂ (M+H)⁺: m/z=487.1; found 487.1.¹H NMR (500 MHz, DMSO-d₆) δ 9.42 (s, 1H), 7.82 (d, J=6.1 Hz, 1H), 7.65(s, 2H), 7.60 (d, J=6.2 Hz, 1H), 7.57-7.50 (m, 1H), 7.28 (t, J=8.7 Hz,2H), 3.23-3.16 (m, 1H), 3.07-3.01 (m, 2H), 2.99-2.91 (m, 1H), 2.90-2.82(m, 1H), 1.91-1.66 (m, 3H), 1.30-1.13 (m, 1H) ppm.

Example 4N-{4-[(3S)-3-Aminopiperidin-1-yl]thieno[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

Step 1. tert-Butyl{(3S)-1-[5-({[2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)thieno[2,3-b]pyridin-4-yl]piperidin-3-yl}carbamate

A solution of 1-chloro-N,N,2-trimethylpropenylamine (88.5 mg, 0.662mmol) in DCM (1.0 mL) was added slowly to a suspension of2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (from step 2 inExample 2, 56.9 mg, 0.236 mmol) in DCM (0.5 mL). The mixture was stirredat room temperature for 2 h. A solution of tert-butyl[(3S)-1-(5-aminothieno[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate (73.3mg, 0.210 mmol) in DCM (2.0 mL), followed by pyridine (162.6 mg, 2.056mmol) was then added and the mixture was stirred at room temperature fora further 2 h. The reaction mixture was then concentrated under reducedpressure and the resulting residue was purified by chromatography onsilica gel (0-100% EtOAc in hexanes) to give the sub-title compound as adark oil (118.2 mg, 98%). LCMS calc. for C₂₇H₂₈F₂N₅O₃S₂ (M+H)⁺:m/z=572.2; found 572.2.

Step 2.N-{4-[(3S)-3-Aminopiperidin-1-yl]thieno[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

TFA (2.0 mL) was added to a solution of tert-butyl{(3S)-1-[5-({[2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)thieno[2,3-b]pyridin-4-yl]piperidin-3-yl}carbamate(118.2 mg, 0.2068 mmol) in DCM (2.0 mL). The mixture was stirred at roomtemperature for 30 min., and then concentrated under reduced pressure.The resulting residue was purified using RP-HPLC (XBridge™ C18 column,eluting with a gradient of MeCN/water containing 0.1% NH₄OH, at flowrate of 30 mL/min.) to afford the title compound as a white solid (33.5mg, 34%). LCMS calc. for C₂₂H₂₀F₂N₅OS₂ (M+H)⁺: m/z=472.1; found 472.1.

Example 55-Amino-N-{7-[(3S)-3-aminopiperidin-1-yl]thieno[3,2-b]pyridin-6-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

Step 1. 6-Nitrothieno[3,2-b]pyridin-7-ol

A solution of N,N,N-tributylbutan-1-aminium nitrate (4.780 g, 15.70mmol) in DCM (20 mL) was added to a solution ofthieno[3,2-b]pyridin-7-ol (Aldrich, 1.545 g, 10.22 mmol) in DCM (15 mL)at −10° C. Trifluoroacetic anhydride (3.524 g, 16.78 mmol) was thenadded dropwise. After stirring at −10° C. for 30 min., the mixture wasallowed to warm to room temperature and stirred for 24 h. The reactionmixture was concentrated under reduced pressure. The resulting residuewas triturated with ether (50 mL), and filtered. The filter cake waswashed with water (100 mL) and ether/MeOH (1:1, 80 mL), and was thendried to give the sub-title compound as a yellow solid (1.56 g, 78%).LCMS calc. for C₇H₅N₂O₃S (M+H)⁺: m/z=197.0; found 197.0.

Step 2. 7-Chloro-6-nitrothieno[3,2-b]pyridine

POCl₃ (20.0 mL) was added to 6-nitrothieno[3,2-b]pyridin-7-ol (1.56 g,7.95 mmol). The mixture was stirred at 110° C. for 3 h. The reactionmixture was then concentrated under reduced pressure. The resultingresidue was dissolved in DCM (150 mL), and a saturated aq. NaHCO₃ (150mL) was added slowly. The organic layer was washed with water (100 mL)and brine (100 mL), then dried over Na₂SO₄ and concentrated underreduced pressure. The residue was purified by chromatography on silicagel (0 to 30% EtOAc in hexanes) to afford the sub-title compound as apale yellow solid (1.39 g, 82%). LCMS calc. for C₇H₄ClN₂O₂S (M+H)⁺:m/z=215.0; found 215.0.

Step 3. tert-Butyl[(3S)-1-(6-nitrothieno[3,2-b]pyridin-7-yl)piperidin-3-yl]carbamate

To a vial containing 7-chloro-6-nitrothieno[3,2-b]pyridine (128.7 mg,0.5996 mmol) and tert-butyl (3S)-piperidin-3-ylcarbamate (Combi-Blocks,297.6 mg, 1.486 mmol), 1-butanol (3.00 mL) was added, followed by DIPEA(179.9 mg, 1.392 mmol). The mixture was stirred at 110° C. for 12 h.After cooling to room temperature, the reaction mixture was concentratedunder reduced pressure. The resulting residue was purified bychromatography on silica gel (0-30% EtOAc in hexanes) to give thesub-title compound as a yellow solid (210.1 mg, 93%). LCMS calc. forC₁₇H₂₃N₄O₄S (M+H)⁺: m/z=379.1; found 379.2.

Step 4. tert-Butyl[(3S)-1-(6-aminothieno[3,2-b]pyridin-7-yl)piperidin-3-yl]carbamate

To a vial containing tert-butyl[(3S)-1-(6-nitrothieno[3,2-b]pyridin-7-yl)piperidin-3-yl]carbamate(210.1 mg, 0.5552 mmol), iron powder (306.1 mg, 5.481 mmol) and NH₄Cl(491.9 mg, 9.196 mmol), EtOH (5.00 mL) was added, followed by water(1.00 mL). The mixture was stirred at 80° C. for 2 h. The reactionmixture was then filtered through a pad of diatomaceous earth. Thediatomaceous earth pad was eluted with a 10% aq. K₃PO₄ (30 mL) and EtOAc(30 mL). The organic layer was washed with brine (30 mL), then driedover Na₂SO₄, and concentrated under reduced pressure. The resultingresidue (197.9 mg) of the sub-title compound was used in the next stepwithout further purification. LCMS calc. for C₁₇H₂₅N₄O₂S (M+H)⁺:m/z=349.2; found 349.2.

Step 5. tert-Butyl{(3S)-1-[6-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)thieno[3,2-b]pyridin-7-yl]piperidin-3-yl}carbamate

1-Chloro-N,N,2-trimethylpropenylamine (76.1 mg, 0.570 mmol) in THF (1.0mL) was added slowly to a solution of5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylicacid (Example 1, step 6, 76.1 mg, 0.214 mmol) in THF (0.5 mL). Themixture was stirred at room temperature for 5 h. A solution oftert-butyl[(3S)-1-(6-aminothieno[3,2-b]pyridin-7-yl)piperidin-3-yl]carbamate (62.3mg, 0.179 mmol) in THF (2.0 mL) was then added, followed by pyridine(135.3 mg, 1.710 mmol), and the mixture was stirred at room temperaturefor a further 2 h. The mixture was then concentrated under reducedpressure and the residue was purified by chromatography on silica gel(0-100% EtOAc in hexanes) to afford the sub-title compound as a darksemi-solid (78.5 mg, 64%). LCMS calc. for C₃₂H₃₇F₂N₆O₅S₂ (M+H)⁺:m/z=687.2; found 687.2.

Step 6.5-Amino-N-{7-[(3S)-3-aminopiperidin-1-yl]thieno[3,2-b]pyridin-6-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

TFA (2.0 mL) was added to a solution of tert-butyl{(3S)-1-[6-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)thieno[3,2-b]pyridin-7-yl]piperidin-3-yl}carbamate(78.5 mg, 0.114 mmol) in DCM (2.0 mL). The mixture was stirred at roomtemperature for 30 min., and then concentrated under reduced pressure.The resulting residue was purified using RP-HPLC (XBridge™ C18 column,eluting with a gradient of MeCN/water containing 0.1% NH₄OH, at flowrate of 30 mL/min.) to afford the title compound as a white solid (28.5mg, 51%). LCMS calc. for C₂₂H₂₁F₂N₆OS₂ (M+H)⁺: m/z=487.1; found 487.1.¹H NMR (500 MHz, DMSO-d₆) δ 9.56 (s, 1H), 7.95 (d, J=5.5 Hz, 1H), 7.66(s, 2H), 7.57-7.50 (m, 1H), 7.49 (d, J=5.5 Hz, 1H), 7.28 (t, J=8.8 Hz,2H), 3.24-3.16 (m, 1H), 3.08-3.01 (m, 1H), 3.01-2.91 (m, 2H), 2.83-2.74(m, 1H), 1.90-1.67 (m, 3H), 1.24-1.10 (m, 1H) ppm.

Example 6N-{7-[(3S)-3-Aminopiperidin-1-yl]thieno[3,2-b]pyridin-6-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

Step 1. tert-Butyl{(3S)-1-[6-({[2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)thieno[3,2-b]pyridin-7-yl]piperidin-3-yl}carbamate

A solution of 1-chloro-N,N,2-trimethylpropenylamine (68.8 mg, 0.515mmol) in DCM (1.0 mL) was added slowly to a suspension of2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (Example 2, step2, 45.4 mg, 0.188 mmol) in DCM (0.5 mL). The mixture was stirred at roomtemperature for 2 h. A solution of tert-butyl[(3S)-1-(6-aminothieno[3,2-b]pyridin-7-yl)piperidin-3-yl]carbamate (58.8mg, 0.169 mmol) in DCM (2.0 mL) was then added, followed by pyridine(123.7 mg, 1.564 mmol) and the mixture was stirred at room temperaturefor a further 2 h. The mixture was concentrated under reduced pressureand the resulting residue was purified by chromatography on silica gel(0-100% EtOAc in hexanes) to give the sub-title compound as a paleyellow oil (92.2 mg, 96%). LCMS calc. for C₂₇H₂₈F₂N₅O₃S₂ (M+H)⁺:m/z=572.2; found 572.2.

Step 2.N-{7-[(3S)-3-aminopiperidin-1-yl]thieno[3,2-b]pyridin-6-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

TFA (2.0 mL) was added to a solution of tert-butyl{(3S)-1-[6-({[2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)thieno[3,2-b]pyridin-7-yl]piperidin-3-yl}carbamate(92.2 mg, 0.161 mmol) in DCM (2.0 mL). The mixture was stirred at roomtemperature for 30 min., and then concentrated under reduced pressure.The resulting residue was purified using RP-HPLC (XBridge™ C18 column,eluting with a gradient of MeCN/water containing 0.15% NH₄OH, at flowrate of 30 mL/min.) to afford the title compound as a white solid (43.9mg, 58%). LCMS calc. for C₂₂H₂₀F₂N₅OS₂ (M+H)⁺: m/z=472.1; found 472.1.

Example 75-Amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

Step 1. 4-Chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine

To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (Ark Pharm, 5.023 g,32.92 mmol) in DCM (150 mL), DMAP (418.1 mg, 3.422 mmol) was added,followed by triethylamine (4.984 g, 49.25 mmol) and benzenesulfonylchloride (6.904 g, 39.09 mmol). After stirring at room temperature for15 h, the mixture was washed with 1 M HCl (100 mL). The organic layerwas washed with saturated aq. NaHCO₃ (100 mL) and brine (100 mL), thendried over Na₂SO₄ and concentrated under reduced pressure. The resultingresidue was purified by chromatography on silica gel (0-100% EtOAc inhexanes) to give the sub-title compound as a pale yellow solid (9.39 g,97%). LCMS calc. for C₁₃H₁₀ClN₂O₂S (M+H)⁺: m/z=293.0; found 293.0.

Step 2. 4-Chloro-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine

A solution of N,N,N-tributylbutan-1-aminium nitrate (4.895 g, 16.08mmol) in DCM (20 mL) was added to a solution of4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (3.038 g, 10.38mmol) in DCM (40 mL) at −10° C. Trifluoroacetic anhydride (3.890 g,18.52 mmol) was then added slowly. After stirring at −10° C. for 30min., the reaction mixture was allowed to warm to room temperature andstirred for 24 h. The reaction mixture was then diluted with DCM (50mL), washed with water (2×75 mL) and brine (75 mL), then dried withNa₂SO₄, and concentrated under reduced pressure. The resulting residuewas purified by chromatography on silica gel (0-100% EtOAc in hexanes)to give the sub-title compound as a pale yellow solid (3284.5 mg, 94%).LCMS calc. for C₁₃H₉ClN₃O₄S (M+H)⁺: m/z=338.0; found 338.0.

Step 3. tert-Butyl{(3S)-1-[5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-3-yl}carbamate

To a vial containing4-chloro-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (714.2 mg,2.115 mmol) and tert-butyl (3S)-piperidin-3-ylcarbamate (Combi-Blocks,645.9 mg, 3.225 mmol), 1-butanol (8.00 mL) was added followed by DIPEA(582.8 mg, 4.509 mmol). The reaction mixture was stirred at 110° C. for12 h. After cooling to room temperature, the reaction mixture wasconcentrated under reduced pressure. The resulting residue was purifiedby chromatography on silica gel (0-50% EtOAc in hexanes) to give thesub-title compound as a yellow solid (719.5 mg, 68%). LCMS calc. forC₂₃H₂₈N₅O₆S (M+H)⁺: m/z=502.2; found 502.2.

Step 4. tert-Butyl{(3S)-1-[5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-3-yl}carbamate

To a vial containing tert-butyl{(3S)-1-[5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-3-yl}carbamate(719.5 mg, 1.434 mmol), iron powder (793.6 mg, 14.21 mmol) and NH₄Cl(1147.6 mg, 21.454 mmol), EtOH (10.00 mL) was added followed by water(2.00 mL). The mixture was stirred at 80° C. for 2 h. The reactionmixture was then filtered through a pad of diatomaceous earth. The padwas eluted with 10% aq. K₃PO₄ (50 mL) and EtOAc (50 mL). The organiclayer was washed with brine (50 mL), then dried over Na₂SO₄, andconcentrated under reduced pressure. The residue was purified bychromatography on silica gel (0-100% EtOAc in hexanes) to give thesub-title compound as a dark solid (491.8 mg, 73%). LCMS calc. forC₂₃H₃₀N₅O₄S (M+H)⁺: m/z=472.2; found 472.2.

Step 5. tert-Butyl{(3S)-1-[5-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-3-yl}carbamate

A solution of 1-chloro-N,N,2-trimethylpropenylamine (115.7 mg, 0.8659mmol) in THF (1.0 mL) was added slowly to a solution of5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylicacid (Example 1, Step 6, 120.4 mg, 0.3379 mmol) in THF (1.0 mL). Themixture was stirred at room temperature for 5 h. A solution oftert-butyl{(3S)-1-[5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-3-yl}carbamate(127.3 mg, 0.2699 mmol) in THF (2.0 mL) was then added, followed bypyridine (227.6 mg, 2.877 mmol) and the mixture was stirred at roomtemperature for a further 12 h. The mixture was then concentrated andthe residue was purified by chromatography on silica gel (0-100% EtOAcin hexanes) to afford the sub-title compound as a yellow solid (194.4mg, 89%). LCMS calc. for C₃₈H₄₂F₂N₇O₇S₂ (M+H)⁺: m/z=810.2; found 810.2.

Step 6.5-Amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

To solution of tert-butyl{(3S)-1-[5-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-3-yl}carbamate(194.4 mg, 0.2400 mmol) in MeOH (2.0 mL), aq. NaOH (1.0 M, 2.0 mL) wasadded followed by THF (2.0 mL). After stirring at room temperature for 5h, the reaction mixture was diluted with EtOAc (50 mL), washed withbrine (50 mL), then dried over Na₂SO₄ and concentrated under reducedpressure. The resulting residue was dissolved in DCM (2.0 mL), and TFA(2.0 mL) was added. The mixture was stirred at room temperature for 30min., and then concentrated under reduced pressure. The resultingresidue was purified using RP-HPLC (XBridge™ C18 column, eluting with agradient of MeCN/water containing 0.15% NH₄OH, at flow rate of 30mL/min.) to afford the title compound as a white solid (46.6 mg, 41%).LCMS calc. for C₂₂H₂₂F₂N₇OS (M+H)⁺: m/z=470.1; found 470.2. ¹H NMR (500MHz, DMSO-d₆) δ 11.49 (s, 1H), 9.49 (s, 1H), 9.04 (s, 1H), 7.64-7.47 (m,3H), 7.35 (d, J=3.3 Hz, 1H), 7.27 (t, J=8.8 Hz, 2H), 6.57 (d, J=3.4 Hz,1H), 3.29-3.23 (m, 1H), 3.10-3.03 (m, 1H), 3.00-2.86 (m, 2H), 2.85-2.77(m, 1H), 1.87-1.79 (m, 1H), 1.79-1.65 (m, 2H), 1.24-1.10 (m, 1H) ppm.

Example 8N-{4-[(3S)-3-Aminopiperidin-1-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

Step 1. tert-Butyl{(3S)-1-[5-({[2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-3-yl}carbamate

A solution of 1-chloro-N,N,2-trimethylpropenylamine (114.1 mg, 0.8539mmol) in DCM (1.0 mL) was added slowly to a suspension of2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (Example 2, Step2, 74.2 mg, 0.308 mmol) in DCM (1.0 mL). The mixture was stirred at roomtemperature for 2 h. A solution of tert-butyl{(3S)-1-[5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-3-yl}carbamate(125.1 mg, 0.2653 mmol) in DCM (2.0 mL) was added, followed by pyridine(217.3 mg, 2.747 mmol), and the mixture was then stirred at roomtemperature for 12 h. The reaction mixture was concentrated underreduced pressure and the resulting residue was purified bychromatography on silica gel (0-100% EtOAc in hexanes) to give thesub-title compound as a dark oil (175.3 mg, 95%). LCMS calc. forC₃₃H₃₃F₂N₆O₅S₂ (M+H)⁺: m/z=695.2; found 695.2.

Step 2.N-{4-[(3S)-3-Aminopiperidin-1-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

To a solution of tert-butyl{(3S)-1-[5-({[2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-3-yl}carbamate(175.3 mg, 0.2523 mmol) in MeOH (2.0 mL), aq. NaOH (1.0 M, 2.0 mL) wasadded, followed by THF (2.0 mL). After stirring at room temperature for5 h, the reaction mixture was diluted with EtOAc (50 mL), washed withbrine (50 mL), dried over Na₂SO₄ and concentrated under reducedpressure. The residue was dissolved in DCM (2.0 mL), and TFA (2.0 mL)was added. The mixture was stirred at room temperature for 30 min., andthen concentrated under reduced pressure. The resulting residue waspurified using RP-HPLC (XBridge™ C18 column, eluting with a gradient ofMeCN/water containing 0.15% NH₄OH, at flow rate of 30 mL/min.) to affordthe title compound as a white solid (59.1 mg, 52%). LCMS calc. forC₂₂H₂₂F₂N₆OS (M+H)⁺: m/z=455.1; found 455.1.

Example 95-Amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

Step 1. 2-(2-Fluoro-4-iodopyridin-3-yl)ethanol

A solution of 2.0 M lithium diisopropylamide in heptane/THF/ethylbenzene(8.10 mL, 16.2 mmol) was added to a solution of 2-fluoro-3-iodopyridine(Ark Pharm, 2.989 g, 13.40 mmol) in THF (50 mL) at −78° C., then themixture was stirred at −78° C. for 90 min. With the temperaturemaintained at −78° C., a solution of 1,3,2-dioxathiolane 2,2-dioxide(2.206 g, 17.77 mmol) in THF (30 mL) was added slowly over a period of20 min., the solution was stirred at −78° C. for a further 20 min., thenallowed to warm to room temperature and stirred for 2 h. The mixture wasthen cooled to 0° C., and 12.0 M aq. HCl (5.0 mL, 60. mmol) was added.The reaction mixture was allowed to warm to room temperature and stirredfor 3 h. Saturated aq. NaHCO₃ (250 mL) was added, then the mixture wasextracted with EtOAc (3×150 mL). The combined extracts were washed withbrine (250 mL), dried over Na₂SO₄ and concentrated under reducedpressure. The residue was purified by chromatography on silica gel(0-100% EtOAc in hexanes) to give the sub-title compound as a whitesolid (3.13 g, 87%). LCMS calc. for C₇H₈FINO (M+H)⁺: m/z=268.0; found268.0.

Step 2. 4-Iodo-2,3-dihydrofuro[2,3-b]pyridine

Potassium phosphate (10.0 g, 47.1 mmol) was added to a solution of2-(2-fluoro-4-iodopyridin-3-yl)ethanol (3.13 g, 11.7 mmol) in1,4-dioxane (100 mL). The mixture was heated under reflux for 36 h. Thereaction mixture was filtered, and the filter cake was washed withEtOAc. The combined filtrates were concentrated under reduced pressure.The residue was dissolved in DCM (100 mL), washed with brine (2×100 mL),dried over Na₂SO₄ and concentrated under reduced. The resulting residue(2.55 g) containing the sub-title compound was used in the next stepdirectly without further purification. LCMS calc. for C₇H₇INO (M+H)⁺:m/z=247.9; found 248.0.

Step 3. 4-Iodo-5-nitro-2,3-dihydrofuro[2,3-b]pyridine

A solution of fuming nitric acid (15.0 mL, 358 mmol) in concentratedsulfuric acid (15.0 mL, 281 mmol) was added slowly over a period of 15min. to a stirred solution of 4-iodo-2,3-dihydrofuro[2,3-b]pyridine(2.237 g, 9.055 mmol) in sulfuric acid (10.0 mL, 188 mmol) at −10° C.The reaction mixture was allowed to warm to room temperature, andstirred for a further 16 h. The reaction mixture was quenched by pouringonto crushed ice and was then extracted with EtOAc (6×100 mL). Theorganic extracts were combined and washed with saturated aq. NaHCO₃(2×300 mL) and brine (300 mL), then dried over Na₂SO₄, and concentratedunder reduced pressure. The residue was purified by chromatography onsilica gel (0-100% EtOAc in hexanes) to give the sub-title compound as apale yellow solid (2.43 g, 92%). LCMS calc. for C₇H₆IN₂O₃(M+H)⁺:m/z=292.9; found 293.0.

Step 4. tert-Butyl[(3S)-1-(5-nitro-2,3-dihydrofuro[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate

EtOH (12.00 mL) was added to a microwave vial containing4-iodo-5-nitro-2,3-dihydrofuro[2,3-b]pyridine (2.05 g, 7.02 mmol),tert-butyl (3S)-piperidin-3-ylcarbamate (Combi-Blocks, 1.489 g, 7.435mmol) and DIPEA (1.836 g, 14.20 mmol). The vial was sealed and themixture was heated at 100° C. under microwave irradiation for 2 h. Thereaction mixture was concentrated under reduced pressure and theresulting residue was purified by chromatography on silica gel (0-100%EtOAc in hexanes) to give the title compound as a yellow solid (2.46 g,96%). LCMS calc. for C₁₇H₂₅N₄O₅ (M+H)⁺: m/z=365.2; found 365.1.

Step 5. tert-Butyl[(3S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate

10% Pd on carbon (108.7 mg, 0.1021 mmol) was added under a nitrogenatmosphere to a solution of tert-butyl[(3S)-1-(5-nitro-2,3-dihydrofuro[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate(411.2 mg, 1.128 mmol) in MeOH (5.00 mL). The reaction mixture waspurged with hydrogen gas and was stirred under hydrogen (1 atm.) for 14h. The reaction mixture was then filtered through a pad of diatomaceousearth. The pad was eluted with further MeOH. The filtrate wasconcentrated under reduced pressure to give the sub-title compound as anoff-white solid (387.9 mg), which was used directly in the next stepwithout further purification. LCMS calc. for C₁₇H₂₇N₄O₃ (M+H)⁺:m/z=335.2; found 335.2.

Step 6. tert-Butyl{(3S)-1-[5-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-2,3-dihydrofuro[2,3-b]pyridin-4-yl]piperidin-3-yl}carbamate

To a mixture of5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylicacid (Example 1, Step 6, 418.2 mg, 1.174 mmol), tert-butyl[(3S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate(377.4 mg, 1.128 mmol) and HATU (1308 mg, 3.440 mmol), DMF (15.0 mL) wasadded, followed by DIPEA (1.00 mL, 5.74 mmol). The mixture was stirredat room temperature for 2 h. The reaction mixture was then diluted withEtOAc (150 mL), washed with saturated aq. NaHCO₃ (150 mL) and brine(2×75 mL), then dried over Na₂SO₄ and concentrated under reducedpressure. The residue was purified by chromatography on silica gel(0-100% EtOAc in hexanes) to give the sub-title compound as a yellowsolid (720.2 mg, 95%). LCMS calc. for C₃₂H₃₉F₂N₆O₆S (M+H)⁺: m/z=673.3;found 673.2.

Step 7.5-Amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

TFA (3.0 mL) was added to a solution of tert-butyl{(3S)-1-[5-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-2,3-dihydrofuro[2,3-b]pyridin-4-yl]piperidin-3-yl}carbamate(720.2 mg, 1.070 mmol) in DCM (3.0 mL). The mixture was stirred at roomtemperature for 30 min. and then concentrated under reduced pressure.The resulting residue was purified using RP-HPLC (XBridge™ C18 column,eluting with a gradient of MeCN/water containing 0.15% NH₄OH, at flowrate of 30 mL/min.) to give the title compound as a white solid (187.7mg, 37%). LCMS calc. for C₂₂H₂₃F₂N₆O₂S (M+H)⁺: m/z=473.1; found 473.2.¹H NMR (500 MHz, DMSO-d₆) δ 8.74 (s, 1H), 7.68-7.39 (m, 3H), 7.26 (t,J=8.8 Hz, 2H), 4.48 (t, J=8.9 Hz, 2H), 3.37 (t, J=8.5 Hz, 2H), 3.14-3.01(m, 1H), 3.00-2.90 (m, 1H), 2.89-2.81 (m, 1H), 2.77-2.69 (m, 1H),2.55-2.50 (m, 1H), 1.83-1.59 (m, 3H), 1.12-1.00 (m, 1H) ppm.

Example 10N-{4-[(3S)-3-Aminopiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

To a mixture of 2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid(Example 2, Step 2, 14.5 mg, 0.0601 mmol), tert-butyl[(3S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate(19.2 mg, 0.0574 mmol) and HATU (72.5 mg, 0.191 mmol), DMF (1.50 mL) wasadded, followed by DIPEA (79.6 mg, 0.616 mmol). The reaction mixture wasstirred at room temperature for 2 h, and then concentrated under reducedpressure. To the residue, DCM (2.0 mL) was added, followed by TFA (2.0mL). The mixture was stirred at room temperature for 30 min., and thenconcentrated under reduced pressure. The resulting residue was purifiedusing RP-HPLC (XBridge™ C18 column, eluting with a gradient ofMeCN/water containing 0.15% NH₄OH, at flow rate of 30 mL/min.) to affordthe title compound as a white solid (5.3 mg, 20%). LCMS calc. forC₂₂H₂₂F₂N₅O₂S (M+H)⁺: m/z=458.1; found 458.1.

Example 11N-{4-[(3S)-3-Aminopiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

Step 1. Methyl 6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylate

To a screw-cap vial equipped with a magnetic stir bar, methyl6-bromo-5-fluoropyridine-2-carboxylate (Frontier Scientific, 200.2 mg,0.8555 mmol) was added followed by2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Combi-Blocks, 310.2 mg, 1.292 mmol), andbis(tri-tert-butylphosphine)palladium (87.5 mg, 0.171 mmol). The vialwas sealed with a PTFE-lined septum, evacuated and backfilled withnitrogen three times. 1,4-Dioxane (3.0 mL) was added via a syringe,followed by DIPEA (0.30 mL, 1.7 mmol) and deoxygenated water (0.1 mL).The mixture was heated at 100° C. for 2 h and was then allowed to coolto room temperature. The mixture was diluted with EtOAc (40 mL), washedwith water (40 mL) and brine (40 mL), then dried over Na₂SO₄, andconcentrated under reduced pressure. The resulting residue was purifiedby chromatography on silica gel (0-50% EtOAc in hexanes) to give thesub-title compound as a white solid (210.2 mg, 92%). LCMS calc. forC₁₃H₉F₃NO₂ (M+H)⁺: m/z=268.1; found 268.0.

Step 2. 6-(2,6-Difluorophenyl)-5-fluoropyridine-2-carboxylic Acid

To a mixture of methyl6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylate (210.2 mg, 0.7867mmol) and lithium hydroxide, monohydrate (162 mg, 3.86 mmol), THF (3.0mL) was added followed by water (1.0 mL). The mixture was heated at 50°C. for 3 h. The reaction mixture was then cooled to 0° C., and 1 M HClwas added slowly until the pH reached 2. The reaction mixture was thendiluted with water (20 mL), extracted with EtOAc (3×20 mL) and thecombined organic layers were washed with brine (30 mL), dried overNa₂SO₄, and concentrated under reduced pressure to yield the sub-titlecompound as a white solid (162.1 mg, 81%). LCMS calc. for C₁₂H₇F₃NO₂(M+H)⁺: m/z=254.0; found 254.0.

Step 3.N-{4-[(3S)-3-aminopiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

To a mixture of 6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylicacid (15.0 mg, 0.0592 mmol), tert-butyl[(3S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate(19.1 mg, 0.0571 mmol) and HATU (73.6 mg, 0.194 mmol), DMF (1.50 mL) wasadded, followed by DIPEA (84.8 mg, 0.656 mmol). The reaction mixture wasstirred at room temperature for 2 h, and then concentrated under reducedpressure. DCM (2.0 mL) was added to the residue, followed by TFA (2.0mL). The mixture was stirred at room temperature for 30 min., and thenconcentrated under reduced pressure. The resulting residue was purifiedusing RP-HPLC (XBridge™ C18 column, eluting with a gradient ofMeCN/water containing 0.15% NH₄OH, at flow rate of 30 mL/min.) to affordthe title compound as a white solid (5.9 mg, 22%). LCMS calc. forC₂₄H₂₃F₃N₅O₂(M+H)⁺: m/z=470.2; found 470.2.

Example 123-Amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

Step 1. Methyl 3-amino-5-fluoropyridine-2-carboxylate

Tin dichloride (45 g, 230 mmol) was added to a solution of5-fluoro-3-nitropyridine-2-carbonitrile (Ark Pharm, 7.2 g, 43 mmol) inEtOH (80 mL). The mixture was stirred at 90° C. for 2 h, and thenconcentrated under reduced pressure. Aq. HCl (10 M; 40 mL, 400 mmol) wasthen added and the mixture was heated under reflux for 6 h. The reactionmixture was then concentrated under reduced pressure and the resultingresidue was dissolved in MeOH (120 mL). Thionyl chloride (7.2 mL, 99mmol) was added. The solution was then stirred at 90° C. for 24 h. Thereaction mixture was concentrated under reduced pressure, diluted withEtOAc (300 mL), washed with a saturated aq. NaHCO₃ (300 mL) and brine(200 mL), dried over Na₂SO₄ and concentrated again under reducedpressure. The resulting residue was purified by chromatography on silicagel (0-100% EtOAc in hexanes) to afford the sub-title compound (4.6 g,63%). LCMS calc. for C₇H₈FN₂O₂(M+H)⁺: m/z=171.0; found 171.1.

Step 2. Methyl 3-amino-6-bromo-5-fluoropyridine-2-carboxylate

To a solution of methyl 3-amino-5-fluoropyridine-2-carboxylate (3.6 g,21 mmol) in MeCN (60 mL), N-bromosuccinimide (4.1 g, 23 mmol) was addedportionwise. After stirring at room temperature for 2 h, the reactionmixture was diluted with EtOAc (200 mL), washed with a saturated aq.NaHCO₃ (200 mL) and brine (200 mL), then dried over Na₂SO₄ andconcentrated under reduced pressure. The resulting residue was purifiedby chromatography on silica gel (0-100% EtOAc in hexanes) to afford thesub-title compound as a pale yellow solid (4.0 g, 76%) LCMS calc. forC₇H₇BrFN₂O₂ (M+H)⁺: m/z=249.0; found 249.0.

Step 3. Methyl3-amino-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylate

To a screw-cap vial equipped with a magnetic stir bar, methyl3-amino-6-bromo-5-fluoropyridine-2-carboxylate (99.6 mg, 0.400 mmol) wasadded, followed by2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Combi-Blocks, 190 mg, 0.80 mmol), andbis(tri-tert-butylphosphine)palladium (40.9 mg, 0.080 mmol). The vialwas sealed with a PTFE-lined septum, evacuated and backfilled withnitrogen three times. 1,4-Dioxane (2.0 mL) was added via a syringe,followed by DIPEA (0.14 mL, 0.80 mmol) and deoxygenated water (0.05 mL).The mixture was heated at 100° C. for 2 h. After cooling to roomtemperature, the mixture was diluted with EtOAc (40 mL) and washed withwater (40 mL) and brine (40 mL), then dried over Na₂SO₄, andconcentrated under reduced pressure. The resulting residue was purifiedby chromatography on silica gel (0-50% EtOAc in hexanes) to give thesub-title compound as a white solid (84.0 mg, 74%). LCMS calc. forC₁₃H₁₀F₃N₂O₂ (M+H)⁺: m/z=283.1; found 283.1.

Step 4. 3-Amino-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylicAcid

To a mixture of methyl3-amino-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylate (84.0 mg,0.298 mmol) and lithium hydroxide, monohydrate (40.2 mg, 0.958 mmol),THF (2.0 mL) was added followed by water (1.0 mL). The mixture washeated at 50° C. for 3 h. The reaction was then cooled to 0° C. for, and1 M HCl was added slowly until the pH reached 2. The reaction mixturewas then diluted with water (20 mL), extracted with EtOAc (3×20 mL), andthe combined organic extract was washed with brine (30 mL), dried overNa₂SO₄, and concentrated under reduced pressure to give the sub-titlecompound as a white solid (68.5 mg, 86%). LCMS calc. for C₁₂H₈F₃N₂O₂(M+H)⁺: m/z=269.0; found 269.0.

Step 5.3-Amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

To a mixture of3-amino-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (15.9mg, 0.0592 mmol), tert-butyl[(3S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate(19.8 mg, 0.0592 mmol) and HATU (72.9 mg, 0.192 mmol) DMF (1.50 mL) wasadded, followed by DIPEA (84.1 mg, 0.651 mmol). The reaction mixture wasstirred at room temperature for 2 h, and then concentrated under reducedpressure. DCM (2.0 mL) was added to the residue, followed by TFA (2.0mL). The mixture was stirred at room temperature for 30 min., and thenconcentrated under reduced pressure. The resulting residue was purifiedusing RP-HPLC (XBridge™ C18 column, eluting with a gradient ofMeCN/water containing 0.15% NH₄OH, at flow rate of 30 mL/min.) to affordthe title compound as a white solid (4.9 mg, 17%). LCMS calc. forC₂₄H₂₄F₃N₆O₂ (M+H)⁺: m/z=485.2; found 485.2. ¹H NMR (500 MHz, DMSO-d₆) δ10.29 (br s, 1H), 8.86 (s, 1H), 7.60 (tt, J=8.3, 6.8 Hz, 1H), 7.40 (brs, 2H), 7.26 (t, J=8.2 Hz, 2H), 7.21 (d, J=11.5 Hz, 1H), 4.47 (t, J=9.0Hz, 2H), 3.34 (t, J=8.5 Hz, 2H), 3.04-2.93 (m, 1H), 2.88-2.78 (m, 1H),2.69-2.57 (m, 1H), 2.54-2.46 (m, 1H), 2.46-2.37 (m, 1H), 1.50-1.17 (m,3H), 0.95-0.78 (m, 1H) ppm.

Example 13N-{4-[(3S)-3-Aminopiperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

Step 1: 6,7-Dihydro-5H-cyclopenta[b]pyridine 1-oxide

mCPBA (10.0 g, 44.6 mmol) was added slowly to a mixture of6,7-dihydro-5H-cyclopenta[b]pyridine (from Aldrich, 5.0 g, 42 mmol) inDCM (50 mL). The reaction mixture was stirred at room temperature for 2h. The solution was then washed with aq. Na₂S₂O₃ (50 mL) and 1 M NaOH(50 mL). The aqueous layer was extracted with DCM (5×70 mL). Thecombined organic layers were dried, filtered and concentrated underreduced pressure to give the sub-title compound (4.5 g, 79%). LCMS calc.for C₈H₁₀NO (M+H)⁺: m/z=136.1. Found: 136.2.

Step 2: 4-Chloro-6,7-dihydro-5H-cyclopenta[b]pyridine

6,7-Dihydro-5H-cyclopenta[b]pyridine 1-oxide (2.5 g, 18 mmol) was mixedwith POCl₃ (20 mL). The reaction mixture was stirred at 120° C. for 3 h.The excess POCl₃ was removed under reduced pressure. The residue wasdiluted in EtOAc (80 mL) and neutralized with aq. Na₂CO₃. Afterfiltration, the aqueous layer was extracted with EtOAc twice. Thecombined organic layers were dried, filtered and concentrated underreduced pressure to give the sub-title compound (2.6 g, 93%). LCMS calc.for C₈H₉ClN (M+H)⁺: m/z=154.0. Found: 154.3.

Step 3: 4-Methoxy-6,7-dihydro-5H-cyclopenta[b]pyridine

A mixture of 4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine (2.8 g, 18mmol), MeOH (20 mL) and sodium methoxide (3.0 g, 56 mmol) was sealed ina pressurized flask and heated at 110° C. for 18 h. The mixture wasdiluted with EtOAc and neutralized with HCl to pH=1. The organic solventwas removed under reduced pressure. The resulting mixture was washedwith ether twice, and then neutralized with Na₂CO₃ solution. The aqueouslayer was extracted twice with EtOAc. The combined organic layers weredried, filtered and concentrated under reduced pressure to give thesub-title compound (1.20 g, 44%). LCMS calc. for C₉H₁₂NO (M+H)⁺:m/z=150.1. Found: 150.2.

Step 4: 4-Methoxy-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine

4-Methoxy-6,7-dihydro-5H-cyclopenta[b]pyridine (2.90 g, 19.4 mmol) wasmixed with concentrated sulfuric acid (17.0 g, 173 mmol) at 0° C., thena mixture of potassium nitrate (5.3 g, 52 mmol) in another portion ofconcentrated sulfuric acid (26.5 g, 270 mmol) was added slowly. Thereaction mixture was heated at 80° C. for 4 h. The crude mixture wasslowly poured onto crushed ice (50 g), and neutralized carefully with50% aq. NaOH to pH 8-9. The resulting mixture was extracted with EtOAcfive times. The combined organic extracts were dried and concentratedunder reduced pressure to give the crude sub-title compound as brown gum(1.56 g, 41%), which was used without further purification. LCMS calc.for C₉H₁₁N₂O₃ (M+H)⁺: m/z=195.1. Found: 195.2.

Step 5: 3-Nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-ol

A mixture of 4-methoxy-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine(1.535 g, 7.905 mmol) in AcOH (2.6 mL) was treated 48% aq. HBr (2.6 mL,23 mmol). The flask containing the mixture was sealed and heated at 130°C. for 40 min., then allowed to cool. The resulting mixture wasconcentrated under reduced pressure, the residue was neutralized topH=7-8 using 50% NaOH with cooling. After further concentrating, theresidue was diluted with MeOH and THF, dried, filtered and concentratedto give the crude sub-title compound as light brown powder, which wasused without further purification. LCMS calc. for C₈H₉N₂O₃(M+H)⁺:m/z=181.1. Found: 181.2.

Step 6: 4-Chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine

A solution of 3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-ol (1.424 g,7.904 mmol) in POCl₃ (11.0 mL) was heated at 110° C. in a sealed flaskunder N₂ for 2 h. The crude mixture was cooled to room temperature, andconcentrated under reduced pressure. The residue was carefully quenchedwith ice, and neutralized with 50% NaOH to pH 7. The resulting mixturewas extracted with EtOAc three times. The combined organic layers weredried, filtered and concentrated under reduced pressure to give thecrude sub-title compound as a brown solid (0.82 g, 52%), which was usedwithout further purification. LCMS calc. for C₈H₈N₂O₂(M+H)⁺: m/z=199.0.Found: 199.2.

Step 7: tert-Butyl[(3S)-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate

A mixture of 4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (40mg, 0.20 mmol), tert-butyl (3S)-piperidin-3-ylcarbamate (81 mg, 0.40mmol) and triethylamine (84 μL, 0.60 mmol) in isopropyl alcohol (0.46mL) was stirred at 100° C. for 30 min. The reaction mixture wasconcentrated under reduced pressure and purified by silica gel columnchromatography (eluting with 0-40% EtOAc in hexanes) to give thesub-title compound as light yellow powder (43 mg, 59%). LCMS calc. forC₁₈H₂₇N₄O₄ (M+H)⁺: m/z=363.2. Found: 363.2.

Step 8: tert-Butyl[(3S)-1-(3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate

A mixture of tert-butyl[(3S)-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate(43 mg, 0.12 mmol), iron powder (106 mg, 1.90 mmol) and NH₄Cl (127 mg,2.37 mmol) in EtOH (0.69 mL) and water (0.11 mL) was heated in a sealedtube at 80° C. for 1 h. The mixture was diluted with EtOAc and theresulting solution was washed with saturated aq. Na₂CO₃, dried overNa₂SO₄, filtered and concentrated under reduced pressure to give thesub-title compound as a brown-orange powder (51 mg, 100%). LCMS calc.for C₁₈H₂₉N₄O₂ (M+H)⁺: m/z=333.2. Found: 333.1.

Step 9: tert-Butyl{(3S)-1-[3-({[2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]piperidin-3-yl}carbamate

tert-Butyl[(3S)-1-(3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate(5.0 mg, 0.015 mmol) was mixed with2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (Example 2, step2, 4.4 mg, 0.018 mmol), HATU (14 mg, 0.038 mmol), DMF (0.035 mL) andDIPEA (5.8 mg, 0.045 mmol). The reaction mixture was stirred at roomtemperature for 1 h. The mixture was filtered, concentrated and purifiedby preparative LC-MS (XBridge™ preparative C18 5 μm 30×10 mm OBD™column, flow rate 60 mL/min., eluting with a gradient of MeCN and waterwith 0.15% NH₄OH) to give the sub-title compound as a colorless gum (4.1mg, 49%). LCMS calc. for C₂₈H₃₂F₂N₅O₃S (M+H)⁺: m/z=556.2. Found: 556.1.

Step 10:N-{4-[(3S)-3-Aminopiperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

tert-Butyl{(3S)-1-[3-({[2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]piperidin-3-yl}carbamate(4 mg, 0.007 mmol) was dissolved in DCM (0.02 mL) and then TFA (0.03 mL,0.4 mmol) was added. The resulting reaction mixture was stirred at roomtemperature for 30 min. and then concentrated to give a residue, whichwas diluted with MeOH and neutralized with small amount of NH₄OH. Themixture was filtered and purified by preparative LC-MS (XBridge™preparative C18 30×10 mm, 5 □m OBD™ column, at flow rate of 60 mL/min.,eluting with a gradient of MeCN and water with 0.15% NH₄OH) to affordthe title compound (1.9 mg, 58%). LCMS calc. for C₂₃H₂₄F₂N₅OS (M+H)⁺:m/z=456.2. Found: 456.1.

Example 145-Amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

A mixture of tert-butyl[(3S)-1-(3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate(15 mg, 0.045 mmol),5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylicacid (19 mg, 0.054 mmol), HATU (43 mg, 0.11 mmol) and DIPEA (24 μL, 0.14mmol) in dry DMF (0.11 mL) was stirred at room temperature for 16 h. Thereaction mixture was concentrated under reduced pressure to give anintermediate, which was treated with TFA (0.070 mL, 0.90 mmol). Theresulting reaction mixture was stirred at room temperature for 1 h thenconcentrated under reduced pressure. The residue was diluted with MeOHand neutralized with small amount of NH₄OH. The mixture was filtered andpurified by preparative LC-MS (XBridge™ preparative C18 5 μm 30×10 mmOBD™ column, flow rate 60 mL/min., eluting with a gradient of MeCN andwater with 1.5% NH₄OH) to give the title compound as a white powder (7.5mg, 35%). LCMS calc. for C₂₃H₂₅F₂N₆OS (M+H)⁺: m/z=471.2. Found: 471.1.¹H NMR (500 MHz, DMSO-d₆) δ 9.24 (s, 1H), 7.61 (s, 2H), 7.57-7.45 (m,1H), 7.36-7.17 (m, 2H), 3.12-2.96 (m, 3H), 2.91 (t, J=9.8 Hz, 1H),2.88-2.70 (m, 4H), 2.66-2.55 (m, 1H), 2.07-1.99 (m, 2H), 1.86-1.56 (m,3H), 1.18-1.01 (m, 1H) ppm.

Example 155-Amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

Step 1: tert-Butyl[(3S)-1-(3-nitro-1-oxido-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate

mCPBA (198 mg, 0.883 mmol) was added slowly to a solution of tert-butyl[(3S)-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate(301 mg, 0.83 mmol) in DCM (1.1 mL) at 0° C. The reaction mixture wasthen stirred at room temperature for 67 h. The mixture was treated withaq. Na₂S₂O₃ and 1 M NaOH, and then stirred for 30 min. at roomtemperature. The reaction mixture was extracted with DCM three times.The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give the sub-title compound (277mg, 88%) as light orange powder, which was used without furtherpurification. LCMS calc. for C₁₈H₂₇N₄O₅ (M+H)⁺: m/z=379.2. Found: 379.2.

Step 2:4-{(3S)-3-[(tert-Butoxycarbonyl)amino]piperidin-1-yl}-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylAcetate

A mixture of Ac₂O (0.90 g, 8.8 mmol) and tert-butyl[(3S)-1-(3-nitro-1-oxido-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate(270 mg, 0.714 mmol) was sealed and heated at 90° C. for 1 h, thenallowed to cool to room temperature. The excess Ac₂O was removed underreduced pressure. The residue was dissolved in DCM, and then poured intoice cold aq. Na₂CO₃. The mixture was extracted with DCM twice. Thecombined extracts were dried, filtered and concentrated under reducedpressure to give a crude product, which was purified by preparativeLC-MS (XBridge™ preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60mL/min., eluting with a gradient of MeCN and water with 0.15% NH₄OH) toprovide the sub-title compound as a yellow powder (65 mg, 22%). LCMScalc. for C₂₀H₂₉N₄O₆ (M+H)⁺: m/z=421.2. Found: 421.3.

Step 3:3-Amino-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylAcetate

A mixture of4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (64 mg, 0.15 mmol), AcOH (0.90 mL), water (0.10 mL) and ironpowder (149 mg, 2.66 mmol) was stirred at room temperature for 20 min.The mixture was diluted with EtOAc and filtered through a short silicagel plug. The filtrate was concentrated under reduced pressure, dilutedwith EtOAc and washed with aq. Na₂CO₃. The organic layer was dried,filtered and concentrated under reduced pressure to give the sub-titlecompound (66 mg) as a yellowish solid, which was used without furtherpurification. LCMS calc. for C₂₀H₃₁N₄O₄ (M+H)⁺: m/z=391.2. Found: 391.1.

Step 4:3-({[5-[(tert-Butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylAcetate

3-Amino-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (20 mg, 0.051 mmol),(5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylicacid (Example 1, step 6, 22 mg, 0.062 mmol), HATU (49 mg, 0.13 mmol),DMF (0.12 mL) and DIPEA (20 mg, 0.15 mmol) were mixed together andstirred at room temperature for 16 h. The mixture was concentrated underreduced pressure and purified by silica gel column chromatography(eluting with 0-100% EtOAc in hexanes) to give the sub-title compound asa colorless gum (30 mg, 80%). LCMS calc. for C₃₅H₄₃F₂N₆O₇S (M+H)⁺:m/z=729.3. Found: 729.1.

Step 5:5-Amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

3-({[5-[(tert-Butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (30 mg, 0.041 mmol) in MeOH (0.59 mL) was mixed with 1.0 M NaOH(0.30 mL, 0.30 mmol) and THF (0.3 mL). The reaction mixture was stirredat room temperature for 25 min. The organic solvents were removed underreduced pressure. The aqueous layer was extracted twice with EtOAc. Thecombined organic layers were dried, filtered and concentrated underreduced pressure to give an intermediate (19 mg). The intermediate wastreated with ice-cold TFA in DCM (4.0 M; 1.0 mL, 4.0 mmol). Afterstirring for 20 min. at room temperature, the reaction mixture wasconcentrated under reduced pressure. The residue was diluted with MeOHand neutralized with small amount of NH₄OH. The resulting mixture wasfiltered and purified by preparative LC-MS (XBridge™ preparative C18 5μm 30×10 mm OBD™ column, flow rate 60 mL/min., eluting with a gradientof MeCN and water with 0.15% NH₄OH) to afford the title compound as twodiastereoisomers.

Diastereoisomer 1. First peak. Retention time 1.786 min., LCMS calc. forC₂₃H₂₅F₂N₆O₂S (M+H)⁺: m/z=487.2; Found: 487.1.

Diastereoisomer 2. Second peak. Retention time 1.875 min., LCMS calc.for C₂₃H₂₅F₂N₆O₂S (M+H)⁺: m/z=487.2; Found: 487.1.

The diastereoisomers correspond to the (7R) and (7S) diastereoisomers ofthe title compound.

Example 16N-{4-[(3S)-3-Aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

Step 1:4-{(3S)-3-[(tert-Butoxycarbonyl)amino]piperidin-1-yl}-3-({[2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-6,7-dihydro-H-cyclopenta[b]pyridin-7-ylAcetate

3-Amino-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (7.0 mg, 0.018 mmol),2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (5.2 mg, 0.022mmol), HATU (17 mg, 0.045 mmol), DMF (0.042 mL) and DIPEA (7.0 mg, 0.054mmol) were mixed together and the mixture was stirred at roomtemperature for 1 h. The mixture was filtered, concentrated and purifiedby preparative LC-MS (XBridge™ preparative C18 5 μm 30×10 mm OBD™column, flow rate 60 mL/min., eluting with a gradient of MeCN and waterwith 0.15% NH₄OH) to give pure sub-title compound as light yellow powder(3.7 mg, 34%). LCMS calc. for C₃₀H₃₄F₂N₅O₅S (M+H)⁺: m/z=614.2. Found:614.1.

Step 2:N-{4-[(3S)-3-Aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

4-{(3S)-3-[(tert-Butoxycarbonyl)amino]piperidin-1-yl}-3-({[2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (4.0 mg, 0.0065 mmol) was mixed with MeOH (77 μL), THF (39 μL)and 1.0 M NaOH (42 μL, 0.042 mmol). The reaction mixture was stirred atroom temperature for 30 min. The organic solvents were removed underreduced pressure. The resulting aqueous solution was diluted with aq.NH₄Cl and extracted twice with EtOAc. The combined organic layers weredried, filtered and concentrated to give an intermediate. Theintermediate was dissolved in a mixture of DCM (0.066 mL) and TFA (0.066mL, 0.86 mmol). The resulting solution was stirred at room temperaturefor 30 min., then concentrated under reduced pressure. The residue wasdiluted with MeOH, neutralized with NH₄OH, filtered and purified bypreparative LC-MS (XBridge™ preparative C18 5 μm 30×10 mm OBD™ column,flow rate 60 mL/min., eluting with a gradient of MeCN and water with0.15% NH₄OH) to give two diastereoisomers of the title compound as whitepowders.

Diastereoisomer 1. First peak. Retention time 1.685 min., LCMS calc. forC₂₃H₂₄F₂N₅O₂S (M+H)⁺: m/z=472.2. Found: 471.1.

Diastereoisomer 2. Second peak. Retention time 1.797 min., LCMS calc.for C₂₃H₂₄F₂N₅O₂S (M+H)⁺: m/z=472.2. Found: 471.1.

The diastereoisomers correspond to the (7R) and (7S) diastereoisomers ofthe title compound.

Example 17 5-Amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-7-methoxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

NaH (0.35 mg, 0.014 mmol) was added to a solution of tert-butyl{(3S)-1-[3-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]piperidin-3-yl}carbamate(4.0 mg, 0.0058 mmol) in THF (0.024 mL) at 0° C. The reaction mixturewas stirred at 0° C. for 1 h and then methyl iodide (2.1 mg, 0.015 mmol)was added. The reaction mixture was stirred at 0° C. for 1 h andquenched with aq. NH₄Cl. The mixture was extracted with EtOAc threetimes. The organic layers were dried, filtered and concentrated underreduced pressure. The residue was purified by preparative LC-MS(XBridge™ preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60mL/min., eluting with a gradient of MeCN and water with 0.15% NH₄OH) togive the intermediate.

The intermediate was dissolved in a mixture of TFA (0.0090 mL, 0.12mmol) in DCM (0.018 mL) and the resulting mixture was allowed to reactat room temperature for 1 h. The reaction mixture was concentrated underreduced pressure, then diluted with MeOH, and neutralized with NH₄OH.After filtration, the crude product was purified by preparative LC-MS(XBridge™ preparative C18 5 um 30×10 mm OBD™ column, flow rate 60mL/min., eluting with a gradient of MeCN and water with 0.15% NH₄OH) togive the title compound as a mixture of diastereoisomers (1.6 mg, 55%).LCMS calc. for C₂₄H₂₇F₂N₆O₂S (M+H)⁺: m/z=501.2. Found: 501.1. Theproduct is a mixture of the (7R) and (7S) diastereoisomers of the titlecompound.

Example 185-Amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-7-cyano-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

Step 1: tert-Butyl{(3S)-1-[3-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-7-cyano-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]piperidin-3-yl}carbamate

To a mixture of tert-butyl{(3S)-1-[3-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]piperidin-3-yl}carbamate(12.0 mg, 0.0175 mmol) and triethylamine (7.3 μL, 0.052 mmol) in DCM(0.12 mL) at 0° C., methanesulfonyl chloride (20.0 mg, 0.175 mmol) wasadded. The reaction mixture was allowed to warm to room temperature andstirred for 3 h, then concentrated to dryness under reduced pressure.The resulting crude mesylate was dissolved in DMF (48 μL), sodiumcyanide (50 mg, 1 mmol) was added, and the mixture was stirred at roomtemperature for 2 h. After filtration, the crude was purified bypreparative LC-MS (XBridge™ preparative C18 5 μm 30×10 mm OBD™ column,flow rate 60 mL/min., eluting with a gradient of MeCN and water with0.15% NH₄OH) to give the sub-title compound as a mixture of twodiastereoisomers (5 mg, 40%). LCMS calc. for C₃₄H₄₀F₂N₇O₅S (M+H)⁺:m/z=696.3. Found: 696.1.

Step 2:5-Amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-7-cyano-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

TFA (0.02 mL, 0.3 mmol) was added to a solution of tert-butyl{(3S)-1-[3-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-7-cyano-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]piperidin-3-yl}carbamate(5.0 mg, 0.0072 mmol) in DCM (0.009 mL). The reaction mixture wasstirred at room temperature for 15 min., then evaporated under reducedpressure. The resulting mixture was diluted with MeOH and neutralizedwith small amount of NH₄OH. After filtration, the crude product waspurified by preparative LC-MS (XBridge™ preparative C18 5 μm 30×10 mmOBD™ column, flow rate 60 mL/min., eluting with a gradient of MeCN andwater with 0.15% NH₄OH) to give the title compound (4 mg) as a mixtureof two diastereoisomers, which was further purified by chiralpreparative LC (Phenomenex Lux® Cellulose-1 column, 21.2×250 mm, 5 mparticle, flow rate 18 mL/min., isocratic eluting with 45% EtOH inhexanes) to give the title compound as two separated diastereoisomers.

Diastereoisomer 1. First peak (0.5 mg). Retention time 1.579 min. LCMScalc. for C₂₄H₂₄F₂N₇OS (M+H)⁺: m/z=496.2. Found: 496.1.

Diastereoisomer 2. Second peak (0.8 mg). Retention time 1.617 min. LCMScalc. for C₂₄H₂₄F₂N₇OS (M+H)⁺: m/z=496.2. Found: 496.1.

The diastereoisomers correspond to the (7R) and (7S) diastereoisomers ofthe title compound.

Example 195-Amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

Step 1: tert-Butyl{(3S)-1-[3-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-7-oxo-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]piperidin-3-yl}carbamate

Dess-Martin periodinane (12 mg, 0.028 mmol) was added to a solution oftert-butyl{(3S)-1-[3-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]piperidin-3-yl}carbamate(15 mg, 0.022 mmol) in DCM (0.098 mL). The reaction mixture was stirredat room temperature for 1 h. The solution was neutralized with 1 M NaOH,diluted with MeOH and filtered. The mixture was then concentrated underreduced pressure and the crude product was purified by preparative LC-MS(XBridge™ preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60mL/min., eluting with a gradient of MeCN and water with 0.15% NH₄OH) togive sub-title compound as off-white powder (7.5 mg, 50%). LCMS calc.for C₃₃H₃₉F₂N₆O₆S (M+H)⁺: m/z=685.3. Found: 685.1.

Step 2: tert-Butyl{(3S)-1-[3-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]piperidin-3-yl}carbamate

Methylmagnesium bromide in THF (3.0 M, 5.8 μL, 0.018 mmol) was added toa solution of tert-butyl{(3S)-1-[3-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-7-oxo-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]piperidin-3-yl}carbamate(3.0 mg, 0.0044 mmol) in THF (0.068 mL), which was stirred under N₂ andcooled in an ice bath. The reaction mixture was slowly allowed to warmedto room temperature over a period of 1 h. EtOAc was added to thereaction mixture, then 1 M HCl was slowly added to adjust the pH to 7.The aqueous layer was extracted twice with EtOAc. The organic extractswere combined, dried over Na₂SO₄, then filtered and concentrated underreduced pressure to give the sub-title compound. LCMS calc. forC₃₄H₄₃F₂N₆O₆S (M+H)⁺: m/z=701.3. Found: 701.1.

Step 3:5-Amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

TFA (0.02 mL, 0.2 mmol) was added to a solution of tert-butyl{(3S)-1-[3-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]piperidin-3-yl}carbamate(4.0 mg, 0.0044 mmol) in DCM (0.01 mL). The reaction mixture was stirredat room temperature for 30 min., and then diluted with MeOH andneutralized with NH₄OH. After filtration, the crude was purified bypreparative LC-MS (Waters SunFire™ preparative C18 5 μm 30×10 mm column,flow rate 60 mL/min., eluting with a gradient of MeCN and water with0.1% TFA) to give the title compound tris-trifluoroacetate salt as twodiastereoisomers.

Diastereoisomer 1. First peak. Retention time 1.282 min. LCMS calc. forC₂₄H₂₇F₂N₆O₂S (M+H)⁺: m/z=501.2. Found: 501.1.

Diastereoisomer 2. Second peak. Retention time 1.381 min. LCMS calc. forC₂₄H₂₇F₂N₆O₂S (M+H)⁺: m/z=501.2. Found: 501.1.

The diastereoisomers correspond to the (7R) and (7S) diastereoisomers ofthe title compound.

Example 205-Amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-7-oxo-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

A solution of tert-butyl{(3S)-1-[3-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-7-oxo-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]piperidin-3-yl}carbamate(2.0 mg, 0.0029 mmol) in DCM (0.009 mL) was treated with TFA (0.01 mL,0.1 mmol). The reaction mixture was stirred at room temperature for 1 h,concentrated and then diluted with MeOH and neutralized with NH₄OH.After filtration, the crude was purified by preparative LC-MS (XBridge™preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60 mL/min., elutingwith a gradient of MeCN and water with 0.15% NH₄OH) to give the titlecompound as white powder (1.3 mg, 92%). LCMS calc. for C₂₃H₂₃F₂N₆O₂S(M+H)⁺: m/z=485.2. Found: 485.1.

Example 21N-{4-[(3S)-3-Aminopiperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

Step 1: tert-Butyl{(3S)-1-[3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]piperidin-3-yl}carbamate

tert-Butyl[(3S)-1-(3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate(5.0 mg, 0.015 mmol),6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (4.6 mg, 0.018mmol), HATU (14 mg, 0.038 mmol), DMF (0.035 mL) and DIPEA (5.8 mg, 0.045mmol) were mixed together and stirred at room temperature for 1 h. Themixture was filtered, concentrated under reduced pressure and purifiedby preparative LC-MS (XBridge™ preparative C18 30×10 mm 5 m OBD™ column,flow rate 60 mL/min., eluting with a gradient of MeCN and water with0.15% NH₄OH) to give the sub-title compound as a colorless gum (4.1 mg,48%). LCMS calc. for C₃₀H₃₃F₃N₅O₃(M+H)⁺: m/z=568.3. Found: 568.1.

Step 2:N-{4-[(3S)-3-Aminopiperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

A solution of tert-butyl{(3S)-1-[3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]piperidin-3-yl}carbamate(4.0 mg, 0.0070 mmol) in DCM (0.02 mL) was treated with TFA (0.03 mL,0.4 mmol). The resulting reaction mixture was stirred at roomtemperature for 30 min. and then concentrated to give a residue, whichwas diluted with MeOH and neutralized with small amount of NH₄OH. Afterfiltration, the crude was purified by preparative LC-MS (XBridge™preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60 mL/min., elutingwith a gradient of MeCN and water with 0.15% NH₄OH) to afford the titlecompound (2.2 mg, 67%). LCMS calc. for C₂₅H₂₅F₃N₅O (M+H)⁺: m/z=468.2.Found: 468.1.

Example 22N-{4-[(3S)-3-Aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

Step 1:4-{(3S)-3-[(tert-Butoxycarbonyl)amino]piperidin-1-yl}-3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylAcetate

3-Amino-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (6.0 mg, 0.015 mmol),6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (4.7 mg, 0.018mmol), HATU (15.0 mg, 0.038 mmol), DMF (0.036 mL) and DIPEA (6.0 mg,0.046 mmol) were mixed together and stirred at room temperature for 1 h.The mixture was filtered, concentrated under reduced pressure, andpurified by preparative LC-MS (XBridge™ preparative C18, 30×10 mm 5 μmOBD™ column, flow rate 60 mL/min., eluting with a gradient of MeCN andwater with NH₄OH) to give the sub-title compound as a colorless gum (4.0mg, 42%). LCMS calc. for C₃₂H₃₅F₃N₅O₅ (M+H)⁺: m/z=626.3. Found: 626.1.

Step 2:N-{4-[(3S)-3-Aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

4-{(3S)-3-[(tert-Butoxycarbonyl)amino]piperidin-1-yl}-3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (4.0 mg, 0.0064 mmol) was mixed with MeOH (76 μL), THF (38 μL)and 1.0 M NaOH (42 μL, 0.042 mmol). The reaction mixture was stirred atroom temperature for 30 min. The organic solvents were removed underreduced pressure. The aqueous layer was diluted with aq. NH₄Cl thenextracted with EtOAc twice. The combined organic layers were dried,filtered and concentrated under reduced pressure to give anintermediate, which was treated with DCM (0.065 mL) and TFA (0.065 mL,0.84 mmol). The mixture was stirred at room temperature for 30 min.,then concentrated under reduced pressure. The residue was diluted withMeOH and neutralized with small amount of NH₄OH. The resulting mixturewas filtered and purified by preparative LC-MS (XBridge™ preparative C185 μm 30×10 mm OBD™ column, flow rate 60 mL/min., eluting with a gradientof MeCN and water with 0.15% NH₄OH) to give two diastereoisomers of thetitle compound as white powders.

Diastereoisomer 1. First peak. Retention time 2.138 min., LCMS calc. forC₂₅H₂₅F₃N₅O₂(M+H)⁺: m/z=484.2. Found: 484.0.

Diastereoisomer 2. Second peak. Retention time 2.219 min., LCMS calc.for C₂₅H₂₅F₃N₅O₂(M+H)⁺: m/z=484.2. Found: 484.0. ¹H NMR (500 MHz,CD₃CN): δ 10.80 (br, 2H), 9.52 (s, 1H), 8.39 (dd, J=8.0, 4.0 Hz, 1H),7.93 (t, J=8.0 Hz, 1H), 4.92 (m, 1H), 3.14 (m, 1H), 3.01 (m, 2H), 2.87(m, 1H), 2.82 (m, 2H), 2.66 (m, 1H), 2.53 (m, 2H), 2.45 (m, 2H), 1.95(m, 1H), 1.54 (m, 1H), 1.43 (m, 1H), 0.95 (m, 1H) ppm.

The diastereoisomers correspond to the (7R) and (7S) diastereoisomers ofthe title compound.

Example 233-Amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

Step 1:3-({[3-Amino-6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate

3-Amino-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (6.0 mg, 0.015 mmol),3-amino-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (4.9mg, 0.018 mmol), HATU (15 mg, 0.038 mmol), DMF (0.036 mL) and DIPEA (6.0mg, 0.046 mmol) were mixed together and stirred at room temperature for16 h. The mixture was filtered, concentrated under reduced pressure, andpurified by preparative LC-MS (XBridge™ preparative C18 5 μm 30×10 mmOBD™ column, flow rate 60 mL/min., eluting with a gradient of MeCN andwater with 0.15% NH₄OH) to give the sub-title compound as a colorlessgum (4 mg, 41%). LCMS calc. for C₃₂H₃₆F₃N₆O₅ (M+H)⁺: m/z=641.3. Found:641.0.

Step 2:3-Amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

3-({[3-Amino-6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (4.0 mg, 0.0062 mmol) was mixed with MeOH (74 μL), THF (37 μL)and 1.0 M NaOH (41 μL, 0.041 mmol). The reaction mixture was stirred atroom temperature for 30 min. The organic solvents were removed underreduced pressure. The aqueous layer was diluted with aq. NH₄Cl, thenextracted twice with EtOAc. The combined organic layers were dried,filtered and concentrated under reduced pressure to give anintermediate, which was treated with DCM (0.064 mL) and TFA (0.064 mL,0.82 mmol). The resulting mixture was stirred at room temperature for 30min., then concentrated under reduced pressure. The residue was dilutedwith MeOH and neutralized with NH₄OH. The resulting mixture was filteredand purified by preparative LC-MS (XBridge™ preparative C18 5 μm 30×10mm OBD™ column, flow rate 60 mL/min., eluting with a gradient of MeCNand water with 0.15% NH₄OH) to give two diastereoisomers of the titlecompound as white powders.

Diastereoisomer 1. First peak. Retention time 1.703 min. LCMS calc. forC₂₅H₂₆F₃N₆O₂(M+H)⁺: m/z=499.2. Found: 499.0.

Diastereoisomer 2. Second peak. Retention time 1.947 min. LCMS calc. forC₂₅H₂₆F₃N₆O₂(M+H)⁺: m/z=499.2. Found: 499.0. ¹H NMR (500 MHz, DMSO-d₆):δ 10.58 (br, 2H), 9.37 (s, 1H), 7.56 (t, J=8.0 1H), 7.52 (br, 2H), 7.35(m, 1H), 7.22 (s, 1H), 7.17 (s, 1H), 5.15 (s, 1H), 4.75 (m, 1H), 3.02(m, 1H), 2.98 (m, 1H), 2.85 (m, 1H), 2.78 (m, 2H), 2.43 (m, 1H), 2.39(m, 1H), 2.24 (m, 1H), 1.75 (m, 1H), 1.40 (m, 1H), 1.22 (m, 2H), 0.79(m, 1H) ppm.

The diastereoisomers correspond to the (7R) and (7S) diastereoisomers ofthe title compound.

Example 245-Amino-N-{4-[3,4-trans-3-amino-4-hydroxypiperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide(Enantiomer 1)

Step 1: Benzyl 3, 6-dihydropyridine-1 (2H)-carboxylate

1,2,3,6-Tetrahydropyridine (4.90 g, 58.9 mmol), DCM (40 mL),N-(benzyloxycarbonyloxy)succinimide (15.2 g, 61.0 mmol) andtriethylamine (10.0 mL, 71.7 mmol) were mixed together and stirred atroom temperature for 16 h. The reaction mixture was diluted with EtOAcand water. The organic layer was dried, filtered and concentrated underreduced pressure. The resulting residue was purified by chromatographyon silica gel eluting with EtOAc in hexanes (0 to 40%) to give thesub-title compound as clear oil. LCMS calc. for C₁₃H₁₆NO₂ (M+H)⁺:m/z=218.1. Found: 218.0.

Step 2: Benzyl 7-oxa-3-azabicyclo[4.1. O]heptane-3-carboxylate

mCPBA (14.6 g, 63.3 mmol) was added slowly to a stirred solution ofbenzyl 3,6-dihydropyridine-1(2H)-carboxylate (12.50 g, 57.5 mmol) in DCM(80 mL) which was cooled in an ice bath. The reaction mixture wasallowed to warm to room temperature and stirred for 16 h. The reactionmixture was then quenched with aq. Na₂CO₃ and the organic layer wasdried over Na₂SO₄, filtered and concentrated under reduced pressure togive the sub-title compound. LCMS calc. for C₁₃H₁₆NO₃ (M+H)⁺: m/z=234.1.Found: 234.0.

Step 3: Benzyl(3R,4R)-3-[(tert-butoxycarbonyl)amino]-4-hydroxypiperidine-1-carboxylateand Benzyl(3S,4S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxypiperidine-1-carboxylate

Benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (13.4 g, 57.4mmol), 14.8 M aq. NH₄OH (200 mL, 2.9 mol) and EtOH (200 mL) were mixedtogether in a sealed flask and heated at 70° C. for 5 h. The solventswere removed under reduced pressure. The residue was diluted with DCM(80 mL), then di-tert-butyl dicarbonate (12.5 g, 57.4 mmol) andtriethylamine (8.0 mL, 57 mmol) were added. The reaction mixture wasstirred at room temperature for 2 h. The solvent was then removed underreduced pressure and the residue was purified by silica gel columnchromatography eluting with EtOAc in hexanes (0-80%) to give thesub-title compound, which was followed by chiral LC-MS separation(Phenomenex Lux® Cellulose-1 column, 21.2×250 mm, 5 micron particle,flow rate 18 mL/min., isocratic eluting with 45% EtOH in hexanes) toafford two enantiomers.

Benzyl3,4-trans-3-[(tert-butoxycarbonyl)amino]-4-hydroxypiperidine-1-carboxylateEnantiomer 1. First peak retention time 7.163 min., LCMS calc. forC₁₈H₂₆N₂O₅Na (M+Na)⁺: m/z=373.2. Found: 373.1. (Tentatively assigned asthe 3S,4S enantiomer).

Benzyl3,4-trans-3-[(tert-butoxycarbonyl)amino]-4-hydroxypiperidine-1-carboxylateEnantiomer 2. Second peak retention time 9.247 min., LCMS calc. forC₁₈H₂₆N₂O₅Na (M+Na)⁺: m/z=373.2. Found: 373.1. (Tentatively assigned asthe 3R,4R enantiomer).

LCMS calc. for C₁₈H₂₆N₂O₅Na (M+Na)+: m/z=373.2. Found: 373.1.

Step 4: tert-Butyl (3,4-trans-4-{[tert-butyl(dimethyl)silyl]oxy}piperidin-3-yl)carbamate(Enantiomer 1)

Benzyl3,4-trans-3-[(tert-butoxycarbonyl)amino]-4-hydroxypiperidine-1-carboxylate(0.50 g, 1.4 mmol) (Enantiomer 1) obtained from chiral separation (step3, peak 1) was mixed with 1H-imidazole (0.11 g, 1.6 mmol), DMAP (0.017g, 0.14 mmol), DCM (15 mL) and tert-butyldimethylsilyl chloride (0.24 g,1.6 mmol). The reaction mixture was stirred at room temperature for 16h. After vacuum filtration, the filtrate was concentrated under reducedpressure, and purified by silica gel column chromatography using EtOAcin hexanes (0-30%) to give an intermediate (0.50 g). The intermediatewas dissolved in EtOAc (5 mL) and MeOH (5 mL) and 10% Pd on carbon (0.10g) was added and the reaction mixture was hydrogenated at 25 psi for 2h. After vacuum filtration, the filtrate was concentrated under vacuumto give the sub-title compound. LCMS calc. for C₁₆H₃₅N₂O₃Si (M+H)⁺:m/z=331.2. Found: 331.3. The stereochemistry of the product wastentatively assigned as (3S,4S).

Step 5: tert-Butyl(1-(3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-3,4-trans-4-{[tert-butyl(dimethyl)silyl]oxy}piperidin-3-yl)carbamate(Enantiomer 1)

A mixture of 4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (40mg, 0.20 mmol), tert-butyl(3,4-trans-4-{[tert-butyl(dimethyl)silyl]oxy}piperidin-3-yl)carbamate(80 mg, 0.24 mmol) (Enantiomer 1) and triethylamine (0.084 mL, 0.60mmol) in isopropyl alcohol (0.50 mL) was stirred at 70° C. for 18 h. Thereaction mixture was concentrated under reduced pressure and purified bysilica gel column chromatography (eluting with 0-40% EtOAc in hexanes)to give an intermediate as light yellow powder (81 mg). The intermediatewas dissolved in AcOH (0.90 mL) and water (0.10 mL). Iron powder (51 mg,0.91 mmol) was added and the reaction mixture was stirred at roomtemperature for 1 h. The solvent was removed under reduced pressure andthe residue was diluted with EtOAc and neutralized with aq. NaHCO₃. Theorganic extract was dried over Na₂SO₄, filtered and concentrated underreduced pressure to give the sub-title compound. LCMS calc. forC₂₄H₄₃N₄O₃Si (M+H)⁺: m/z=463.3. Found: 463.1. The stereochemistry of theproduct was tentatively assigned as (3S,4S).

Step 6: 5-Amino-N-{4-[(3,4-trans-3-amino-4-hydroxypiperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide(Enantiomer 1)

A mixture containing tert-Butyl(1-(3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-3,4-trans-4-{[tert-butyl(dimethyl)silyl]oxy}piperidin-3-yl)carbamate(Enantiomer 1) (0.010 g, 0.022 mmol),5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylicacid (0.0085 g, 0.024 mmol), HATU (0.033 g, 0.086 mmol), DMF (0.15 mL)and DIPEA (0.011 g, 0.088 mmol) was stirred at room temperature for 18h. The reaction mixture was diluted with EtOAc and washed with aq. NaOH.The organic extract concentrated under reduced pressure, and the residuewas purified by silica gel column chromatography (eluting with 0-100%EtOAc in hexanes) to give an intermediate (8 mg). The intermediate wastreated with HCl in dioxane (4.0 M; 2.5 mL, 10 mmol) and stirred at roomtemperature for 1 h then concentrated under reduced pressure. Theresidue was dissolved in MeOH, neutralized with aq. NH₄OH, and purifiedby preparative LC-MS (XBridge™ preparative C18 5 μm 30×10 mm OBD™column, flow rate 60 mL/min., eluting with a gradient of MeCN and waterwith 0.15% NH₄OH) to afford the title compound. LCMS calc. forC₂₃H₂₅F₂N₆O₂S (M+H)⁺: m/z=487.2. Found: 487.1. The stereochemistry ofthe product was tentatively assigned as (3S,4S).

Example 255-Amino-N-{4-[3,4-trans-3-amino-4-hydroxypiperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide(Enantiomer 2)

Step 1: tert-Butyl (3,4-trans-4-{[tert-butyl(dimethyl)silyl]oxy}piperidin-3-yl)carbamate(Enantiomer 2)

Benzyl3,4-trans-3-[(tert-butoxycarbonyl)amino]-4-hydroxypiperidine-1-carboxylate(0.50 g, 1.4 mmol) (Enantiomer 2) obtained from chiral separation(Example 24, step 3, peak 2) was mixed with 1H-imidazole (0.11 g, 1.6mmol), DMAP (0.017 g, 0.14 mmol), DCM (15 mL) andtert-butyldimethylsilyl chloride (0.24 g, 1.6 mmol). The reactionmixture was stirred at room temperature for 16 h, then filtered byvacuum filtration, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography eluting with EtOAc inhexanes (0-30%) to give an intermediate (0.55 g). The intermediate wasdissolved in a mixture of EtOAc (5 mL) and MeOH (5 mL), 10% Pd on carbon(0.10 g) was added, and the reaction mixture was hydrogenated at 25 psifor 2 h. The reaction mixture was then filtered by vacuum filtrationthrough diatomaceous earth, the filtrate was concentrated under reducedpressure to give the sub-title compound. LCMS calc. for C₁₆H₃₅N₂O₃Si(M+H)⁺: m/z=331.2. Found: 331.3. The stereochemistry of the product wastentatively assigned as (3R,4R).

Step 2: tert-Butyl1-(3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-3,4-trans-4-{[tert-butyl(dimethyl)silyl]oxy}piperidin-3-yl)carbamate(Enantiomer 2)

A mixture of 4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (40mg, 0.20 mmol), tert-butyl(3,4-trans-4-{[tert-butyl(dimethyl)silyl]oxy}piperidin-3-yl)carbamate(Enantiomer 2) (80 mg, 0.24 mmol) and triethylamine (0.084 mL, 0.60mmol) in isopropyl alcohol (0.5 mL) was stirred at 70° C. for 16 h. Thereaction mixture was concentrated under vacuum and purified by silicagel column chromatography (0-40% EtOAc in hexanes) to give anintermediate as light yellow powder (69.8 mg). The intermediate wasdissolved in AcOH (0.90 mL) and water (0.10 mL). Iron powder was added(51 mg, 0.91 mmol) and the reaction mixture was stirred at roomtemperature for 1 h. The solvent was removed under vacuum and theresidue was diluted with EtOAc and neutralized with aq. NaHCO₃. Theorganic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure to give the sub-title compound. LCMS calc. forC₂₄H₄₃N₄O₃Si (M+H)⁺: m/z=463.3. Found: 463.1. The stereochemistry of theproduct was tentatively assigned as (3R,4R).

Step 3: 5-Amino-N-{4-[3,4-trans-3-amino-4-hydroxypiperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide(Enantiomer 2)

A mixture containing tert-butyl1-(3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-3,4-trans-4-{[tert-butyl(dimethyl)silyl]oxy}piperidin-3-yl)carbamate(Enantiomer 2) (0.010 g, 0.022 mmol),5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylicacid (0.0085 g, 0.024 mmol), HATU (0.033 g, 0.086 mmol), DMF (0.15 mL)and DIPEA (0.011 g, 0.088 mmol) was stirred at room temperature for 16h. The reaction mixture was diluted with EtOAc and washed with aq. NaOH.The organic extract was concentrated under vacuum, and the residue waspurified by silica gel column chromatography (eluting with 0-100% EtOAcin hexanes) to give the an intermediate (8 mg), which was treated withHCl in dioxane (4.0 M; 2.5 mL, 10 mmol). The resulting mixture wasstirred at room temperature for 1 h then concentrated under reducedpressure. The residue was dissolved in MeOH, neutralized with aq. NH₄OH,and purified by preparative LC-MS (XBridge™ preparative C18 5 μm 30×10mm OBD™ column, flow rate 60 mL/min., eluting with a gradient of MeCNand water with 0.15% NH₄OH) to provide the title compound. LCMS calc.for C₂₃H₂₅F₂N₆O₂S (M+H)⁺: m/z=487.2. Found: 487.1. ¹H NMR (500 MHz,DMSO-d₆) δ 9.22 (s, 1H), 7.60 (s, 2H), 7.54-7.44 (m, 1H), 7.22 (t, J=8.7Hz, 2H), 6.49 (s, 1H), 4.61 (d, J=2.9 Hz, 1H), 3.18-3.07 (m, 1H), 3.02(m, 3H), 2.94-2.86 (m, 2H), 2.79 (t, J=7.7 Hz, 2H), 2.72-2.59 (m, 2H),2.06-1.98 (m, 2H), 1.84-1.74 (m, 1H), 1.70-1.57 (m, 1H) ppm. Thestereochemistry of the product was tentatively assigned as (3R,4R).

Example 265-Amino-N-{4-[(3,4-cis-3-amino-4-hydroxypiperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide(Enantiomer 1)

Step 1: Benzyl 3,7-cis-2-oxohexahydro[1,3]oxazolo[4,5-c]pyridine-5(4H)-carboxylate(Enantiomer 1)

Benzyl3,4-trans-3-[(tert-butoxycarbonyl)amino]-4-hydroxypiperidine-1-carboxylate(Enantiomer 1) (0.50 g, 1.4 mmol) obtained from chiral separation(Example 24, step 3, peak 1) was mixed with DCM (12 mL), triethylamine(0.30 mL, 2.1 mmol) and methanesulfonyl chloride (0.21 g, 1.8 mmol). Thereaction mixture was stirred at room temperature for 18 h and thenquenched with aq. NaHCO₃. The aqueous layer was extracted with DCM threetimes. The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under vacuum to give the mesylate intermediate. Themesylate was then mixed with pyridine (10 mL) and heated at 120° C. for2 h. After concentrated under vacuum, the resulting residue was purifiedby silica gel column chromatography (eluting with 50-100% EtOAc inhexanes) to give the sub-title compound. LCMS calc. for C₁₄H₁₇N₂O₄(M+H)⁺: m/z=277.1. Found: 277.1. The stereochemistry of the product wastentatively assigned as (3aS,7aR).

Step 2: tert-Butyl 3,7-cis2-oxohexahydro[1,3]oxazolo[4,5-c]pyridine-3(2H)-carboxylate(Enantiomer 1)

Benzyl3,7-cis-2-oxohexahydro[1,3]oxazolo[4,5-c]pyridine-5(4H)-carboxylate(Enantiomer 1) (0.35 g, 1.3 mmol) was dissolved in DCM (6.0 mL),followed by the addition of triethylamine (0.50 mL, 3.6 mmol), DMAP(0.016 g, 0.13 mmol) and di-tert-butyl dicarbonate (0.31 g, 1.4 mmol).The reaction mixture was stirred at room temperature for 18 h thenconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluting with 0-80% EtOAc in hexanes) to givean intermediate. The intermediate was mixed with EtOAc (10 mL) and MeOH(10 mL), and a mixture of 10% Pd on carbon (0.20 g). The resultingmixture was hydrogenated at 25 psi for 1 h. The catalyst was removed byvacuum filtration. The clear filtrate was concentrated under vacuum togive the sub-title compound. LCMS calc. for C₁₁H₁₉N₂O₄ (M+H)⁺:m/z=243.1. Found: 243.1. The stereochemistry of the product wastentatively assigned as (3aS,7aR).

Step 3: tert-Butyl 3,7-cis-(3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-2-oxohexahydro[1,3]oxazolo[4,5-c]pyridine-3(2H)-carboxylate (Enantiomer 1)

A mixture of 4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (40mg, 0.20 mmol), tert-butyl3,7-cis-2-oxohexahydro[1,3]oxazolo[4,5-c]pyridine-3(2H)-carboxylate (58mg, 0.24 mmol) (Enantiomer 1) and triethylamine (0.084 mL, 0.60 mmol) inisopropyl alcohol (0.50 mL) was stirred at 70° C. for 18 h. The mixturewas concentrated and purified by silica gel column chromatography(eluting with 20-80% EtOAc in hexanes) to give an intermediate as ayellow powder (31 mg). The intermediate was dissolved in AcOH (0.90 mL,16 mmol) and water (0.10 mL). Iron powder (51 mg, 0.91 mmol) was added,and the reaction mixture was stirred at room temperature for 1 h. Thesolvent was removed under vacuum and the residue was diluted with EtOAcand neutralized with aq. NaHCO₃. The organic extract was dried overNa₂SO₄, filtered and concentrated under reduced pressure to give thesub-title compound. LCMS calc. for C₁₉H₂₇N₄O₄ (M+H)⁺: m/z=375.2. Found:375.1. The stereochemistry of the product was tentatively assigned as(3aS,7aR).

Step 4: 5-Amino-N-{4-[3,4-cis-3-amino-4-hydroxypiperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide(Enantiomer 1)

A mixture containing tert-butyl3,7-cis-5-(3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-2-oxohexahydro[1,3]oxazolo[4,5-c]pyridine-3(2H)-carboxylate(0.010 g, 0.027 mmol),5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylicacid (0.010 g, 0.029 mmol), HATU (0.041 g, 0.11 mmol), DMF (0.15 mL) andDIPEA (0.014 g, 0.11 mmol) was stirred at room temperature for 18 h. Thereaction mixture was diluted with EtOAc and washed with aq. NaOH. Thecombined organic extract was concentrated under reduced pressure, andthe residue was purified by silica gel column chromatography (elutingwith 0-100% EtOAc in hexanes) to give an intermediate (7 mg). Theintermediate was dissolved in MeOH (0.38 mL) and cesium carbonate (0.050g, 0.15 mmol) was added. The resulting mixture was heated at 80° C. for30 min., then filtrated and concentrated under reduced pressure. Theresidue was dissolved in TFA (0.50 mL, 6.5 mmol) and the reactionmixture was stirred at room temperature for 1 h. The solvent was removedunder reduced pressure, and the residue was dissolved in MeOH,neutralized with aq. NH₄OH. The crude product was purified bypreparative LC-MS (XBridge™ preparative C18 5 μm 30×10 mm OBD™ column,flow rate 60 mL/min., eluting with a gradient of MeCN and water with0.15% NH₄OH) to afford the title compound. LCMS calc. for C₂₃H₂₅F₂N₆O₂S(M+H)⁺: m/z=487.2. Found: 487.1. The stereochemistry of the product wastentatively assigned as (3S,4R).

Example 275-Amino-N-{4-[3,4-cis-3-amino-4-hydroxypiperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide(Enantiomer 2)

Step 1: Benzyl 3,7-cis-2-oxohexahydro[1,3]oxazolo[4,5-c]pyridine-5(4H)-carboxylate(Enantiomer 2)

Benzyl3,4-trans-3-[(tert-butoxycarbonyl)amino]-4-hydroxypiperidine-1-carboxylate(0.50 g, 1.4 mmol) (Enantiomer 2) obtained from chiral separation(Example 24, step 3, peak 2) was mixed with DCM (12 mL), triethylamine(0.30 mL, 2.1 mmol) and methanesulfonyl chloride (0.21 g, 1.8 mmol) andthe reaction mixture was stirred at room temperature for 18 h. Themixture was quenched with aq. NaHCO₃. The aqueous layer was extractedwith DCM three times. The combined organic extracts were dried overNa₂SO₄, filtered and concentrated under reduced pressure to give amesylate intermediate. The mesylate was then mixed with pyridine (10 mL,100 mmol) and heated at 120° C. for 2 h, then the reaction mixture wasconcentrated reduced pressure. The residue was purified by silica gelcolumn chromatography (eluting with 50-100% EtOAc in hexanes) to givethe sub-title compound. LCMS calc. for C₁₄H₁₇N₂O₄ (M+H)⁺: m/z=277.1.Found: 277.1. The stereochemistry of the product was tentativelyassigned as (3aR,7aS).

Step 2: tert-Butyl 3, 7-cis-2-oxohexahydro[1,3]oxazolo[4,5-c]pyridine-3(2H)-carboxylate (Enantiomer 2)

A mixture containing benzyl3,7-cis-2-oxohexahydro[1,3]oxazolo[4,5-c]pyridine-5(4H)-carboxylate(0.32 g, 1.2 mmol) (Enantiomer 2), DCM (10 mL), triethylamine (0.18 mL,1.3 mmol), DMAP (0.014 g) and di-tert-butyl dicarbonate (0.28 g, 1.3mmol) was stirred at room temperature for 18 h, then concentrated underreduced pressure. The mixture was purified by silica gel columnchromatography (eluting with 0-80% EtOAc in hexanes) to give anintermediate. The intermediate was mixed with EtOAc (10 mL) of and MeOH(10 mL), and a and 10% Pd on carbon (0.20 g). The resulting mixture washydrogenated at 25 psi for 1 h. The catalyst was removed by vacuumfiltration. The clear filtrate was concentrated under vacuum to give thesub-title compound. LCMS calc. for C₁₁H₁₉N₂O₄ (M+H)⁺: m/z=243.1. Found:243.1. The stereochemistry of the product was tentatively assigned as(3aR,7aS).

Step 3: tert-Butyl 3,7-cis-5-(3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-2-oxohexahydro[1,3]oxazolo[4,5-c]pyridine-3(2H)-carboxylate (Enantiomer 2)

A mixture of 4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (40mg, 0.20 mmol), tert-butyl3,7-cis-2-oxohexahydro[1,3]oxazolo[4,5-c]pyridine-3(2H)-carboxylate (58mg, 0.24 mmol) (Enantiomer 2) and triethylamine (0.084 mL, 0.60 mmol) inisopropyl alcohol (0.50 mL) was stirred at 70° C. for 18 h. The reactionmixture was concentrated under reduced pressure and the resultingresidue was purified by silica gel column chromatography (eluting with0-80% EtOAc/hexanes) to give an intermediate as light yellow powder. Theintermediate was dissolved into AcOH (0.90 mL, 16 mmol) and water (0.10mL), and iron powder (51 mg, 0.91 mmol) was added. The reaction mixturewas stirred at room temperature for 1 h. The solvent was removed underreduced pressure and the residue was diluted with EtOAc and neutralizedwith aq. NaHCO₃. The organic extract was dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give the sub-title compound. LCMScalc. for C₁₉H₂₇N₄O₄ (M+H)⁺: m/z=375.2. Found: 375.1. Thestereochemistry of the product was tentatively assigned as (3aR,7aS).

Step 4: 5-Amino-N-{4-[3,4-cis-3-amino-4-hydroxypiperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide(Enantiomer 2)

A mixture containing tert-butyl3,7-cis-5-(3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-2-oxohexahydro[1,3]oxazolo[4,5-c]pyridine-3(2H)-carboxylate(Enantiomer 2) (0.010 g, 0.027 mmol),5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylicacid (0.010 g, 0.029 mmol), HATU (0.041 g, 0.11 mmol), DMF (0.15 mL) andDIPEA (0.014 g, 0.11 mmol) was stirred at room temperature for 18 h. Thereaction mixture was diluted with EtOAc and washed with aq. NaOH. Theorganic extract was concentrated under reduced pressure, and theresulting residue was purified by silica gel column chromatography(eluting with 0-100% EtOAc in hexanes) to give an intermediate (7 mg).The intermediate was dissolved in MeOH (0.38 mL) and cesium carbonate(0.050 g, 0.15 mmol) was added. The resulting mixture was heated at 80°C. for 30 min., then filtered, and concentrated under reduced pressure.The residue was dissolved in TFA (0.50 mL, 6.5 mmol) and the resultingmixture was stirred at room temperature for 1 h. The solvent was removedunder reduced pressure, and the residue was dissolved in MeOH,neutralized with aq. NH₄OH and then purified by preparative LC-MS(XBridge™ preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60mL/min., eluting with a gradient of MeCN and water with 0.15% NH₄OH) toafford the title compound. LCMS calc. for C₂₃H₂₅F₂N₆O₂S (M+H)⁺:m/z=487.2. Found: 487.1. The stereochemistry of the product wastentatively assigned as (3S,4R).

Example 285-Amino-N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

Step 1. tert-Butyl(4R)-4-{(1R,2R)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-1-hydroxy-2-methyl-3-oxopropyl}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate

To a solution of (R)-3-(1-oxopropyl)-4-benzyl-2-oxazolidinone (Aldrich,2.0 g, 8.6 mmol) in DCM (60 mL) at −40° C., a solution of TiCl₄ in DCM(1.0 M, 10.0 mL, 10.0 mmol) was added. The mixture was stirred at −40°C. for 10 min., then DIPEA (3.7 mL, 21 mmol) was added. The reactionmixture was allowed to warm to 0° C. and stirred for 20 min. A solutionof tert-butyl (4R)-4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate(Aldrich, 2.0 g, 8.7 mmol) in DCM (20 mL) was then added dropwise andthe resulting mixture was stirred for 1.5 h. The reaction was quenchedby the addition of a saturated aq. NH₄Cl and the mixture was extractedwith EtOAc. The organic extract was washed with brine, dried over MgSO₄,and concentrated under reduced pressure. The residue was purified bychromatography on silica gel (0-40% EtOAc in hexanes) to give thesub-title compound as the major product (5:2) in 87% yield (3.44 g).LCMS calc. for C₂₄H₃₄N₂NaO₇ (M+Na)⁺: m/z=485.2; found 485.1.

Step 2. tert-butyl(4R)-4-((1R,2R)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methyl-3-oxopropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate

To a solution of tert-butyl(4R)-4-{(1R,2R)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-1-hydroxy-2-methyl-3-oxopropyl)}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate(2.0 g, 4.3 mmol) in DCM (40 mL) at −40° C., 2,6-lutidine (0.90 mL, 7.8mmol) was added, followed by tert-butyldimethylsilyltrifluoromethanesulfonate (1.4 mL, 6.0 mmol). The mixture was stirred at−40° C. for 2 h. The reaction mixture was diluted with EtOAc, washedwith a saturated aq. NaHCO₃ and brine, then dried over MgSO₄, andconcentrated under reduced pressure. The residue was purified bychromatography on silica gel (0-20% EtOAc in hexanes) to afford thesub-title compound (2.2 g, 88%). LCMS calc. for C₃₀H₄₉N₂O₇Si (M+H)⁺:m/z=577.3; found 577.3.

Step 3. tert-Butyl(4R)-4-((1R,2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxy-2-methylpropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate

LiBH₄ (0.25 g, 11 mmol) was added to a mixture of tert-butyl(4R)-4-((1R,2R)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methyl-3-oxopropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate(2.2 g, 3.8 mmol) and EtOH (0.67 mL, 11 mmol) in THF (40 mL) at −30° C.The mixture was allowed to warm to 0° C. and stirred for 3 h. Thereaction mixture was then diluted with ether and 1N NaOH was added. Theresulting mixture was extracted with EtOAc. The organic extract waswashed with brine, dried over MgSO₄, and concentrated under reducedpressure. The residue was purified by chromatography on silica gel(0-20% EtOAc in hexanes) to afford the sub-title compound (1.2 g, 78%).LCMS calc. for C₁₅H₃₄NO₃Si (M+H-Boc)⁺: m/z=304.2; found 304.2.

Step 4. tert-Butyl(4R)-4-((1R,2S)-3-azido-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate

To a mixture of tert-butyl(4R)-4-((1R,2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxy-2-methylpropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate(1.2 g, 3.0 mmol), DIAD (1.2 mL, 5.9 mmol) and PPh₃ (1.6 g, 5.9 mmol) inTHF (20 mL), diphenylphosphonic azide (1.3 mL, 5.9 mmol) was added. Themixture was stirred at room temperature overnight. The reaction mixturewas concentrated under reduced pressure. The residue was purified bychromatography on silica gel (0-15% EtOAc in hexanes) to provide thesub-title compound (1.09 g, 86%). LCMS calc. for C₁₅H₃₃N₄O₂Si(M+H-Boc)⁺: m/z=329.2; found 329.2.

Step 5. tert-Butyl[(1R,2R,3S)-4-azido-2-{[tert-butyl(dimethyl)silyl]oxy}-1-(hydroxymethyl)-3-methylbutyl]carbamate

To a solution of tert-butyl(4R)-4-((1R,2S)-3-azido-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate(1.09 g, 2.6 mmol) in EtOH (15 mL), pyridinium p-toluenesulfonate (1.3g, 5.2 mmol) was added. The mixture was heated under reflux for 2 days.After cooling to room temperature, the reaction mixture was concentratedunder reduced pressure. The residue was dissolved in DCM (25 mL), andDIPEA (0.67 mL, 3.8 mmol) was added followed by di-tert-butyldicarbonate (0.67 g, 3.1 mmol). The mixture was stirred at roomtemperature for 5 h, and then concentrated under reduced pressure. Theresidue was purified by chromatography on silica gel (0-25% EtOAc inhexanes) to afford the sub-title compound (0.56 g, 56%). LCMS calc. forC₁₂H₂₉N₄O₂Si (M+H-Boc)⁺: m/z=289.2; found 289.2.

Step 6.(2R,3R,4S)-5-Azido-2-[(tert-butoxycarbonyl)amino]-3-{[tert-butyl(dimethyl)silyl]oxy}-4-methylpentylmethanesulfonate

To a solution of tert-butyl[(1R,2R,3S)-4-azido-2-{[tert-butyl(dimethyl)silyl]oxy}-1-(hydroxymethyl)-3-methylbutyl]carbamate(0.56 g, 1.4 mmol) in pyridine (7.3 mL) at 0° C., methanesulfonylchloride (0.14 mL, 1.9 mmol) was added followed by DMAP (0.04 g, 0.3mmol). After stirring at 0° C. for 1 h, the mixture was diluted withEtOAc, washed with saturated aq. NaHCO₃ and brine, then dried over MgSO₄and concentrated under reduced pressure. The residue was purified bychromatography on silica gel (0-25% EtOAc in hexanes) to afford thesub-title compound (0.59 g, 88%). LCMS calc. for C₁₃H₃₁N₄O₄SSi(M+H-Boc)⁺: m/z=367.2; found 367.2.

Step 7. tert-butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate

A solution of(2R,3R,4S)-5-azido-2-[(tert-butoxycarbonyl)amino]-3-{[tert-butyl(dimethyl)silyl]oxy}-4-methylpentylmethanesulfonate (0.59 g, 1.3 mmol) in MeOH (10 mL) was deoxygenatedwith N₂ for 20 min. DIPEA (0.55 mL, 3.2 mmol) was added, followed by 10wt % Pd on carbon (0.1 g, 0.1 mmol). The mixture was hydrogenated at 1atm. for 2 h, and then filtered. The filtrate was concentrated to affordthe sub-title compound (0.43 g, 98%). LCMS calc. for C₁₇H₃₇N₂O₃Si(M+H)⁺: m/z=345.3; found 345.2. ¹H NMR (500 MHz, CDCl₃) δ 4.35 (bs, 1H),3.32 (dt, J=13.1, 6.3 Hz, 1H), 3.25 (d, J=12.3 Hz, 1H), 3.04 (t, J=8.8Hz, 1H), 2.94 (ddd, J=13.1, 4.1, 1.5 Hz, 1H), 2.33 (dd, J=12.6, 10.5 Hz,1H), 2.24 (dd, J=13.1, 10.9 Hz, 1H), 1.76 (bs, 1H), 1.55 (tdd, J=8.9,6.7, 4.2 Hz, 1H), 1.41 (s, 9H), 0.92 (d, J=6.6 Hz, 3H), 0.87 (s, 9H),0.07 (d, J=10.3 Hz, 6H) ppm.

Step 8: tert-Butyl((3R,4R,5S)-1-(3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate

A mixture of 4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (40mg, 0.20 mmol), tert-butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(83 mg, 0.24 mmol) and triethylamine (0.084 mL, 0.60 mmol) in isopropylalcohol (0.50 mL) was stirred at 70° C. for 18 h. The reaction mixturewas concentrated under reduced pressure and purified by silica gelcolumn chromatography (eluting with 20-80% EtOAc in hexanes) to give anintermediate as a yellow powder (43 mg). The intermediate was dissolvedin EtOH (1.0 mL) and water (0.10 mL). Iron powder (51 mg, 0.91 mmol) andNH₄Cl (54 mg, 1.0 mmol) were added and the reaction mixture was stirredat 80° C. for 1 h. The solvent was removed under reduced pressure andthe residue was diluted with EtOAc and DCM. After vacuum filtration, theclear filtrate was concentrated under reduced pressure to give thesub-sub-title compound. LCMS calc. for C₂₅H₄₅N₄O₃Si (M+H)⁺: m/z=477.3.Found: 477.1.

Step 9:5-Amino-N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

A mixture containing tert-butyl((3R,4R,5S)-1-(3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(0.020 g, 0.042 mmol),5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylicacid (0.016 g, 0.046 mmol), HATU (0.064 g, 0.17 mmol), DMF (0.29 mL) andDIPEA (0.022 g, 0.17 mmol) was stirred at room temperature for 18 h. Thereaction mixture was diluted with EtOAc and washed with NaOH solution.The combined organic extract was concentrated under reduced pressure,and the residue was purified by silica gel column chromatography(eluting with 0-100% EtOAc in hexanes) to give an intermediate (8 mg).The intermediate was treated with HCl in dioxane (4.0 M; 4.8 mL, 19mmol) at room temperature for 1 h. The reaction mixture was concentratedunder reduced pressure and the residue was dissolved in MeOH,neutralized with NH₄OH solution, and purified by preparative LC-MS(XBridge™ preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60mL/min., eluting with a gradient of MeCN and water with 0.15% NH₄OH) togive the title compound. LCMS calc. for C₂₄H₂₇F₂N₆O₂S (M+H)⁺: m/z=501.2.Found: 501.1.

Example 295-Amino-N-{7-[3,4-trans-3-amino-4-hydroxypiperidin-1-yl]thieno[3,2-b]pyridin-6-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide(Enantiomer 2)

Step 1: tert-Butyl (1-(6-aminothieno[3, 2-b]pyridin-7-yl)-3,4-trans-4-{[tert-butyl(dimethyl)silyl]oxy}piperidin-3-yl)carbamate(Enantiomer 2)

A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (Example 5, step 2,43 mg, 0.20 mmol), tert-butyl((3R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}piperidin-3-yl)carbamate(Enantiomer 2) (Example 25, step 1, 80 mg, 0.24 mmol) and triethylamine(0.084 mL, 0.60 mmol) in isopropyl alcohol (0.50 mL) was stirred at 70°C. for 18 h. The reaction mixture was concentrated and purified bysilica gel column chromatography (eluting with 20-40% EtOAc in hexanes)to give an intermediate as light yellow powder. The intermediate wasdissolved in AcOH (0.90 mL, 16 mmol) and water (0.10 mL). Iron powder(51 mg, 0.91 mmol) was added and the reaction mixture was stirred atroom temperature for 1 h. The solvent was removed under reduced pressureand the residue was diluted with EtOAc and neutralized with aq. NaHCO₃.The organic extract was dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give the sub-title compound. LCMS calc. forC₂₃H₃₉N₄O₃SSi (M+H)⁺: m/z=479.2. Found: 479.1. The stereochemistry ofthe product was tentatively assigned as (3R,4R).

Step 2: 5-Amino-N-{7-[3,4-trans-3-amino-4-hydroxypiperidin-1-yl]thieno[3,2-b]pyridin-6-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide(Enantiomer 2)

A mixture containing tert-butyl((3R,4R)-1-(6-aminothieno[3,2-b]pyridin-7-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}piperidin-3-yl)carbamate(Enantiomer 2) (0.010 g, 0.022 mmol),5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylicacid (0.0085 g, 0.024 mmol), HATU (0.033 g, 0.086 mmol), DMF (0.15 mL)and DIPEA (0.011 g, 0.088 mmol) was stirred at room temperature for 18h. The reaction mixture was diluted with EtOAc and washed with aq. NaOH.The combined organic extract was concentrated under reduced pressure,and the residue was purified by silica gel column chromatography(eluting with 0-100% EtOAc in hexanes) to give an intermediate (8 mg).The intermediate was treated with HCl in dioxane (4.0 M; 2.5 mL, 10mmol) and stirred at room temperature for 1 h. The solution wasevaporated under reduced pressure, the residue was dissolved in MeOH,neutralized with aq. NH₄OH, and purified by preparative LC-MS (XBridge™preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60 mL/min., elutingwith a gradient of MeCN and water with 0.15% NH₄OH) to afford the titlecompound. LCMS calc. for C₂₂H₂₁F₂N₆O₂S₂ (M+H)⁺: m/z=503.1. Found: 503.1.The stereochemistry was tentatively assigned as (3R,4R).

Example 305-Amino-N-{7-[3,4-cis-3-amino-4-hydroxypiperidin-1-yl]thieno[3,2-b]pyridin-6-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide(Enantiomer 2)

Step 1: tert-Butyl3,7-cis-5-(6-aminothieno[3,2-b]pyridin-7-yl)-2-oxohexahydro[1,3]oxazolo[4,5-c]pyridine-3(2H)-carboxylate (Enantiomer 2)

A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (43.2 mg, 0.201mmol), tert-butyl3,7-cis-2-oxohexahydro[1,3]oxazolo[4,5-c]pyridine-3(2H)-carboxylate(Enantiomer 2) (Example 27 step 2, 58 mg, 0.24 mmol) and triethylamine(0.084 mL, 0.60 mmol) in isopropyl alcohol (0.50 mL) was stirred at 70°C. for 18 h. The reaction mixture was concentrated under reducedpressure and purified by silica gel column chromatography (eluting with0-80% EtOAc in hexanes) to give an intermediate as light yellow powder(81 mg). The intermediate was dissolved in AcOH (0.90 mL, 16 mmol) andwater (0.10 mL). Iron powder (51 mg, 0.91 mmol) was added and thereaction mixture was stirred at room temperature for 1 h. The solventwas removed under reduced pressure and the residue was diluted withEtOAc, then neutralized with aq. NaHCO₃. The organic extract was driedover Na₂SO₄, filtered and concentrated under reduced pressure to givethe sub-title compound. LCMS calc. for C₁₈H₂₃N₄O₄S (M+H)⁺: m/z=391.1.Found: 391.1. The stereochemistry of the product was tentativelyassigned as (3aR,7aS).

Step 2: 5-Amino-N-{7-[(3R,4S)-3-amino-4-hydroxypiperidin-1 yl]thieno[3,2-b]pyridin-6-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide(Enantiomer 2)

A mixture containing tert-butyl(3aR,7aS)-5-(6-aminothieno[3,2-b]pyridin-7-yl)-2-oxohexahydro[1,3]oxazolo[4,5-c]pyridine-3(2H)-carboxylate(Enantiomer 2) (0.010 g, 0.027 mmol),5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylicacid (0.010 g, 0.029 mmol), HATU (0.041 g, 0.11 mmol), DMF (0.15 mL) andDIPEA (0.014 g, 0.11 mmol) was stirred at room temperature for 18 h. Thereaction mixture was diluted with EtOAc and washed with aq. NaOH. Thecombined organic extract was concentrated under reduced pressure, andthe residue was purified by silica gel column chromatography (elutingwith 0-100% EtOAc in hexanes) to give an intermediate (8 mg). Theintermediate was dissolved in MeOH (0.38 mL) and cesium carbonate (0.050g, 0.15 mmol) was added. The resulting mixture was heated at 80° C. for30 min., then filtered and concentrated under reduced pressure. Theresidue was dissolved in TFA (0.50 mL, 6.5 mmol) and the resultingmixture was stirred at room temperature for 1 h. The solvent was removedunder reduced pressure, and the residue was dissolved in MeOH,neutralized with NH₄OH solution and then purified by preparative LC-MS(XBridge™ preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60mL/min., eluting with a gradient of MeCN and water with 0.15% NH₄OH) togive the title compound. LCMS calc. for C₂₆H₂₁F₂N₆O₂S₂ (M+H)⁺:m/z=503.1. Found: 503.1. The stereochemistry of the product wastentatively assigned as (3R,4S).

Example 315-Amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

Step 1. 3-(3-Chloropropyl)-2-fluoro-4-iodopyridine

Lithium diisopropylamide in THF (2.0 M; 12 mL, 24 mmol) was added to amixture of 2-fluoro-3-iodopyridine (Alfa Aesar, 5.0 g, 22 mmol) in THF(50 mL) at −78° C. The solution was stirred at −78° C. for 1 h, then asolution of 1-chloro-3-iodo-propane, (5.0 g, 24 mmol) in 15 mL THF wasadded dropwise. The reaction mixture was stirred at −78° C. for 30 min.,then allowed to warm to room temperature. The reaction mixture wasquenched with aq.NH₄Cl and extracted with EtOAc. The combined organicextract was dried over Na₂SO₄ and concentrated under reduced pressure.The residue was purified by column chromatography on silica gel usingCombiFlash® apparatus, eluting with 0 to 50% EtOAc/hexanes, to give thesub-title compound (6.2 g, 92%). LCMS calc. for C₈H₉ClFIN (M+H)⁺:m/z=299.9. Found: 300.1.

Step 2. 5-Iodo-1,2,3,4-tetrahydro-1,8-naphthyridine

A mixture of 3-(3-chloropropyl)-2-fluoro-4-iodopyridine (5.0 g, 17mmol), NH₄OH (100 mL, 800 mmol), ammonium acetate (18 g, 230 mmol),potassium iodide (5.5 g, 33 mmol), potassium carbonate (12 g, 87 mmol)and DMF (26 mL) was heated at 60° C. for 8 h. The mixture allowed tocool, and diluted with EtOAc. The layers were separated and the organiclayer was washed with brine, dried with MgSO₄, then concentrated underreduced pressure. The residue was purified by column chromatography onsilica gel using CombiFlash® apparatus, eluting with 0 to 50% EtOAc inhexanes, to give the sub-title compound (3.0 g, 69% yield). LCMS calc.for C₈H₁₀IN₂ (M+H)⁺: m/z=261.0; Found: 261.1.

Step 3. 5-Iodo-6-nitro-1,2, 3, 4-tetrahydro-1,8-naphthyridine

Fuming nitric acid (0.5 mL, 10 mmol) was added a mixture of5-iodo-1,2,3,4-tetrahydro-1,8-naphthyridine (1.0 g, 3.8 mmol) insulfuric acid (10 mL) at 0° C. The reaction was allowed to warm to roomtemperature and stirred for 30 min. The mixture was poured intoice-water and neutralized with 3 M aq. NaOH. The resulting solidprecipitate was collected by filtration, washed with water and dried togive the sub-title compound (0.50 g, 43%). LCMS calc. forC₈H₉IN₃O₂(M+H)⁺: m/z=306.0; Found: 306.1.

Step 4. tert-Butyl [(3S)-1-(3-nitro-5, 6,7,8-tetrahydro-1,8-naphthyridin-4-yl)piperidin-3-yl]carbamate

A mixture of 5-iodo-6-nitro-1,2,3,4-tetrahydro-1,8-naphthyridine (0.50g, 1.6 mmol), tert-butyl (3S)-piperidin-3-ylcarbamate (0.39 g, 2.0mmol), DIPEA (0.64 g, 5.0 mmol) and 1-butanol (6 mL) was heated at 140°C. for 14 h, then allowed to cool. The solvent was removed under reducedpressure, then the residue was diluted with EtOAc and washed with aq.Na₂CO₃ solution. The organic layer was washed with water and brine,dried and concentrated under reduced pressure. The residue was purifiedby column chromatography on silica gel using CombiFlash® apparatus,eluting with 10 to 90% EtOAc in hexanes, to give the sub-title compound(0.55 g, 89%). LCMS calc. for C₁₈H₂₈N₅O₄ (M+H)⁺: m/z=378.2; Found:378.1.

Step 5. tert-Butyl5-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6-nitro-3,4-dihydro-1, 8-naphthyridine-1 (2H)-carboxylate

A mixture of tert-butyl[(3S)-1-(3-nitro-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)piperidin-3-yl]carbamate(0.55 g, 1.4 mmol), di-tert-butyl dicarbonate (0.35 g, 1.6 mmol), DMAP(0.18 g, 1.4 mmol) and MeCN (10 mL) was stirred at room temperature for2 h. The reaction mixture was concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel usingCombiFlash® apparatus, eluting with 20-100% EtOAc in hexanes, to give0.60 g (86%) of sub-title compound as a white solid. LCMS calc. forC₂₃H₃₆N₅O₆ (M+H)⁺: m/z=478.3; Found: 478.1.

Step 6. tert-Butyl6-amino-5-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-3,4-dihydro-1,8-naphthyridine-1 (2H)-carboxylate

Iron powder (0.26 g, 4.6 mmol) was added to a mixture containingtert-butyl5-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6-nitro-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (0.60 g, 1.2 mmol), AcOH (9 mL), and water (1 mL). Thereaction mixture was stirred at room temperature for 2 h. The solutionwas filtered and the filtrate was concentrated under reduced pressure.The residue was diluted with EtOAc (50 mL) and filtered. The filtratewas neutralized with saturated aq. NaHCO₃. The organic layer was washedwith brine, dried with Na₂SO₄ and concentrated under reduced pressure togive the sub-title compound (0.51 g, 90%). LCMS calc. for C₂₃H₃₈N₅O₄(M+H)⁺: m/z=448.3; Found: 448.1.

Step 7. 5-Amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-5, 6,7,8-tetrahydro-1,8-naphthyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

A mixture of tert-butyl6-amino-5-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (0.049 g, 0.11 mmol),5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylicacid (0.039 g, 0.11 mmol) and HATU (0.063 g, 0.16 mmol) in DMF (2 mL),and DIPEA (0.021 g, 0.16 mmol) was stirred at 50° C. for 2 h. Thereaction mixture was diluted with EtOAc and washed with aq. NaHCO₃,water and brine. The organic extract was dried with Na₂SO₄, concentratedand the resulting residue was purified by preparative LC-MS (XBridge™preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60 mL/min., elutingwith a gradient of MeCN and water with 0.1% TFA) to give a Boc-protectedintermediate, LCMS (M+1): 786.1. The intermediate was treated with 50%TFA in DCM (2 mL) and the resulting mixture stirred at room temperaturefor 1 h. The solvent was removed under reduced pressure. The residue waspurified by preparative LC-MS (XBridge™ preparative C18 5 μm 30×10 mmOBD™ column, flow rate 60 mL/min., eluting with a gradient of MeCN andwater with 0.15% NH₄OH) to afford the title compound (5 mg, 10%). LCMScalc. for C₂₃H₂₆F₂N₇OS (M+H)⁺: m/z=486.2; Found: 486.1. ¹H NMR (DMSO-d₆,300 MHz): δ 9.24 (s, 1H), 7.99 (s, 3H), 7.56 (m, 3H), 7.28 (t, J=8.4 Hz,2H), 6.63 (br s, 1H), 3.35-3.65 (m, 5H), 3.20 (m, 4H), 2.70 (m, 2H),2.00 (m, 1H), 1.78 (m, 3H), 1.42 (m, 1H) ppm.

Example 323-Amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

A mixture containing tert-butyl 6-amino-5-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-3,4-dihydro-1,8-naphthyridine-1 (2H)-carboxylate(0.030 g, 0.067 mmol),3-[(tert-butoxycarbonyl)amino]-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylicacid (0.022 g, 0.060 mmol), HATU (0.04 g, 0.1 mmol), DMF (2 mL), andDIPEA (0.021 g, 0.16 mmol) was stirred at 50° C. for 2 h. The reactionmixture was diluted with EtOAc and washed with aq. NaHCO₃, water andbrine. The organic extract was dried with Na₂SO₄ then concentrated underreduced pressure. The resulting residue was purified by preparativeLC-MS (XBridge™ preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60mL/min., eluting with a gradient of MeCN and water with 0.1% TFA) togive a Boc-protected intermediate, LCMS (M+H): 798.1. The intermediatewas treated with 50% TFA in DCM (2 mL) and stirred at room temperaturefor 1 h. The solvent was removed under reduced pressure. The resultingresidue was purified using preparative LC-MS (XBridge™ preparative C18 5μm 30×10 mm OBD™ column, flow rate 60 mL/min., eluting with a gradientof MeCN and water with 0.15% NH₄OH) to afford the title compound (4 mg,13%). LCMS calc. for C₂₅H₂₇F₃N₇O (M+H)⁺: m/z=498.2; Found: 498.2. ¹H NMR(DMSO-d₆, 300 MHz): δ 10.31 (s, 1H), 8.80 (s, 1H), 7.60 (m, 1H), 7.35(br s, 2H), 7.20 (m, 2H), 6.23 (s, 1H), 3.33 (s, 3H), 3.09 (m, 2H), 2.82(m, 2H), 2.62 (m, 2H), 1.66 (m, 2H), 1.17 (m, 2H), 1.05 (m, 1H), 0.80(m, 1H) ppm.

Example 33N-{4-[(3S)-3-Aminopiperidin-1-yl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

A mixture containing tert-butyl6-amino-5-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (0.049 g, 0.11 mmol),6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (0.028 g, 0.11mmol) and HATU (0.063 g, 0.16 mmol) DIPEA (0.021 g, 0.16 mmol) and DMF(2 mL), was stirred at 50° C. for 2 h. The reaction mixture was dilutedwith EtOAc and washed with aq. NaHCO₃, water and brine. The organicextract was dried with Na₂SO₄ and concentrated under reduced pressure.The resulting residue was purified by preparative LC-MS (XBridge™preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60 mL/min., elutingwith a gradient of MeCN and water with 0.1% TFA) to give a Boc-protectedintermediate, LCMS (M+H): 782.1. The intermediate was treated with 50%TFA in DCM (2 mL) and stirred at room temperature for 1 h. The solventwas removed under reduced pressure. The resulting residue was purifiedusing preparative LC-MS (XBridge™ preparative C18 5 μm 30×10 mm OBD™column, flow rate 60 mL/min., eluting with a gradient of MeCN and waterwith 0.15% NH₄OH) to afford the title compound (5 mg, 10%). LCMS calc.for C₂₅H₂₆F₃N₆O (M+H)⁺: m/z=483.2; Found: 483.1. ¹H NMR (DMSO-d₆, 300MHz): δ 10.23 (s, 1H), 8.35 (m, 1H), 8.23 (t, J=9.0 Hz, 1H), 8.06 (br s,4H), 7.70 (m, 1H), 7.37 (m, 2H), 3.33 (s, 3H), 2.90-3.10 (m, 4H), 2.67(m, 2H), 1.77 (m, 3H), 1.54 (m, 2H), 1.29 (m, 1H) ppm.

Example 345-Amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-1H-pyrazolo[3,4-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

Step 1. 1-(4-Methoxybenzyl)-1H-pyrazol-5-amine

Hydrazine (10 mL, 320 mmol) was added over 10 min. to a vigorouslystirred solution of 2-propenenitrile (22.3 mL, 339 mmol) in EtOH (100mL), which was cooled in an ice-water bath to below 20° C. Afterstirring for 20 h, the reaction mixture was cooled in an ice-water bath,and 4-methoxybenzaldehyde (41.1 mL, 338 mmol) was added slowly. Thereaction mixture was stirred at room temperature for 60 h. The solutionwas concentrated under reduced pressure and the residue was dissolved inisopropyl alcohol (100 mL). NaOH (7 g, 200 mmol) was added and theresulting mixture was heated at 120° C. for 2 h. The solution wasconcentrated under reduced pressure and the residue was diluted withwater and EtOAc. The layers were separated and the aqueous layer wasthen extracted with further EtOAc. The combined organic extract waswashed with 1 M HCl. The HCl layers were combined and the pH wasadjusted to 14 using NaOH. The resulting slurry was extracted with DCM.The DCM layers were dried over Na₂SO₄, filtered and concentrated underreduced pressure to afford 21 g of the sub-title compound (30%). LCMScalc. for C₁₁H₁₄N₃O (M+H)⁺: m/z=204.1; Found: 204.2.

Step 2. Ethyl 4-hydroxy-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

A mixture of 1-(4-methoxybenzyl)-1H-pyrazol-5-amine (3 g, 10 mmol) and(ethoxymethylene)propanedioic acid, diethyl ester (3.8 g, 18 mmol) washeated at 120° C. for 1.5 h, then allowed to cool. After cooling, themixture was concentrated and the resulting residue was purified withCombiFlash eluting with 0-30% EtOAc in hexanes to give an intermediate,LCMS (M+H): 374.1. The intermediate was dissolved in diphenyl ether (5mL). The resulted solution was heated at 240° C. in microwave reactorfor 1 h 20 min. After cooling, the solid crashed out was filtered andwashed with hexanes to afford 4.0 g (80%) of the sub-title compound.LCMS calc. for C₁₇H₁₈N₃O₄ (M+H)⁺: m/z=328.1; Found: 328.1.

Step 3. Ethyl 4-chloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

To a solution of ethyl1-(4-methoxybenzyl)-4-oxo-4,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylate(4.0 g, 13 mmol) in 1,2-dichloroethane (9.8 mL) was added POCl₃ (2.4 mL,26 mmol). The resulting mixture was heated at 90° C. for 3 h. Aftercooling, the most volatile were removed by vacuum, and the residue wasdiluted with EtOAc and washed with aq. Na₂CO₃ solution. The organiclayer was washed water and brine, dried and concentrated under reducedpressure. The residue was purified by column chromatography on silicagel using CombiFlash® apparatus, eluting with 10 to 60% EtOAc inhexanes, to give the sub-title compound (3.9 g, 95%). LCMS calc. forC₁₇H₁₇ClN₃O₃(M+H)⁺: m/z=346.1; Found: 346.1.

Step 4. Ethyl4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

A mixture of ethyl4-chloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate(1.5 g, 4.3 mmol), tert-butyl (3S)-piperidin-3-ylcarbamate (1.0 g, 5.0mmol) and DIPEA (0.84 g, 6.5 mmol) in 1-butanol (10 mL) was heated to140° C. for 14 h, then allowed to cool. The mixture was concentratedunder reduced pressure, and the resulting residue was diluted with EtOAcand washed with aq. NaHCO₃. The organic extract was washed with waterand brine, dried and concentrated under reduced pressure. The residuewas purified by column chromatography on silica gel using CombiFlash®apparatus, eluting with 20-100% EtOAc in hexanes, to give the sub-titlecompound (1.9 g, 86%). LCMS calc. for C₂₇H₃₆N₅O₅ (M+H)⁺: m/z=510.3;Found: 510.2.

Step 5.4-{(3S)-3-[(tert-Butoxycarbonyl)amino]piperidin-1-yl}-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid

Water (5 mL) and lithium hydroxide (1.5 g, 63 mmol) were added to asolution of ethyl 4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate(1.9 g, 3.7 mmol) in MeOH (5 mL) and THF (5 mL). The mixture heated at50° C. with stirring for 2 h. The mixture was allowed to cool to roomand concentrated under reduced pressure. The residue was neutralizedwith 2N HCl and extracted twice with EtOAc. The organic extract wasdried with Na₂SO₄ and concentrated under reduced pressure to give thesub-title compound (1.6 g (89%). LCMS calc. for C₂₅H₃₂N₅O₅ (M+H)⁺:m/z=482.2; Found: 482.1.

Step 6. tert-Butyl{(3S)-1-[5-[(tert-butoxycarbonyl)amino]-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]piperidin-3-yl}carbamate

A mixture of4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid (1.0 g, 2.1 mmol), diphenylphosphonic azide (0.58 mL, 2.7 mmol) andDIPEA (0.72 mL, 4.2 mmol) in tert-butyl alcohol (20 mL) heated underreflux overnight. The solution was then evaporated under reducedpressure. The resulting residue was dissolved in DCM, washed with 1 Maq. NaOH and brine, then dried over Na₂SO₄ and evaporated under reducedpressure. The residue was purified by column chromatography on silicagel using CombiFlash® apparatus, eluting with 0 to 50% EtOAc/hexanes, togive the sub-title compound as a brown oil (0.50 g, 44%). LCMS calc. forC₂₉H₄₁N₆O₅ (M+H)⁺: m/z=553.3; Found: 553.2.

Step 7. tert-Butyl {(3S)-1-[5-amino-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]piperidin-3-yl}carbamate

A mixture of tert-butyl{(3S)-1-[5-[(tert-butoxycarbonyl)amino]-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]piperidin-3-yl}carbamate(0.50 g, 0.90 mmol) and HCl in dioxane (4.0 M; 10 mL, 40 mmol) wasstirred at room temperature for 2 h. The solution was then evaporatedunder reduced pressure. The resulting residue was dissolved in THF (10mL), and di-tert-butyl dicarbonate (0.20 g, 0.92 mmol) in THF (5 mL) andtriethylamine (0.37 g, 3.6 mmol) were added. The mixture was stirred atroom temperature for 3 h. The reaction mixture was then diluted withEtOAc and the resulting solution was washed with aq. NaHCO₃ and brine.The organic layer was then dried over Na₂SO₄ and concentrated underreduced pressure. The residue was purified by column chromatography onsilica gel using CombiFlash® apparatus, eluting with 20 to 100% EtOAc inhexanes, to give 0.30 g (73%) of the sub-title compound. LCMS calc. forC₂₄H₃₃N₆O₃ (M+H)⁺: m/z=453.3; Found: 453.1.

Step 8. 5-Amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-1H-pyrazolo[3,4-b]pyridin-5-yl}-2-(2, 6-difluorophenyl)-1,3-thiazole-4-carboxamide

A mixture containing tert-butyl{(3S)-1-[5-amino-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]piperidin-3-yl}carbamate(0.050 g, 0.11 mmol),5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylicacid (0.043 g, 0.12 mmol), HATU (0.063 g, 0.16 mmol), DIPEA (0.021 g,0.16 mmol) and DMF (2 mL) was stirred at 50° C. for 2 h, then allowed tocool. The reaction mixture was diluted with EtOAc and the resultingsolution was washed with aq. NaHCO₃, water and brine, then dried withNa₂SO₄, and concentrated under reduced pressure. The residue waspurified by preparative LC-MS (XBridge™ preparative C18 5 μm 30×10 mmOBD™ column, flow rate 60 mL/min., eluting with a gradient of MeCN andwater with 0.1% TFA) to give a Boc-protected intermediate (15 mg), LCMS(M+H): 791.1. The intermediate was treated with 50% TFA in DCM (2 mL)and stirred at room temperature for 1 h. The solvent was removed underreduced pressure. The residue was purified by preparative LC-MS(XBridge™ preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60mL/min., eluting with a gradient of MeCN and water with 0.15% NH₄OH) toafford the title compound (5 mg, 10%). LCMS calc. for C₂₁H₂₁F₂N₈OS(M+H)⁺: m/z=471.1; Found: 471.1.

Example 35N-{4-[(3S)-3-aminopiperidin-1-yl]-1H-pyrazolo[3,4-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

A mixture containing tert-butyl{(3S)-1-[5-amino-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]piperidin-3-yl}carbamate(0.050 g, 0.11 mmol), 2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylicacid (0.029 g, 0.12 mmol), HATU (0.063 g, 0.16 mmol), DIPEA (0.021 g,0.16 mmol) and DMF (2 mL) was stirred at 50° C. for 2 h. The reactionmixture was diluted with EtOAc and the resulting solution was washedwith aq. NaHCO₃, water and brine, then dried with Na₂SO₄, andconcentrated under reduced pressure. The resulting residue was purifiedby preparative LC-MS (XBridge™ preparative C18 5 μm 30×10 mm OBD™column, flow rate 60 mL/min., eluting with a gradient of MeCN and waterwith 0.1% TFA) to give a Boc-protected intermediate (10 mg), LCMS (M+H):676.1. The intermediate was treated with TFA (2 mL) and stirred at 50°C. for 2 h. The solvent was then evaporated under reduced pressure andthe resulting residue was purified by preparative LC-MS (XBridge™preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60 mL/min., elutingwith a gradient of MeCN and water with 0.15% NH₄OH) to afford the titlecompound (4 mg, 10%). LCMS calc. for C₂₁H₂₀F₂N₇OS (M+H)⁺: m/z=456.1;Found: 456.1. ¹H NMR (DMSO-d₆, 300 MHz): δ 8.67 (s, 1H), 8.57 (s, 1H),8.14 (s, 1H), 7.62 (m, 1H), 7.32 (m, 2H), 3.53 (d, J=8.2 Hz, 1H), 3.40(m, 2H), 3.27 (m, 2H), 3.00 (t, J=9.3 Hz, 1H), 2.85 (m, 2H), 1.76 (d,J=9.3 Hz, 1H), 1.56 (m, 2H), 1.14 (m, 1H) ppm.

Example 365-Amino-N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

Step 1. 1-tert-Butyl 2-methyl (2S)-5-oxopyrrolidine-1, 2-dicarboxylate

Thionyl chloride (5.6 mL, 77 mmol) was added dropwise over 10 min. to asolution of (2S)-5-oxopyrrolidine-2-carboxylic acid (Aldrich, 5.0 g, 39mmol) in MeOH (30.0 mL) at 0° C. The mixture was allowed to warm to roomtemperature and stirred for 2 h. The reaction was concentrated underreduced pressure and the resulting residue was dissolved in EtOAc (25mL). After slow addition of triethylamine (5.4 mL, 39 mmol), the mixturewas filtered. DMAP (0.48 g, 3.9 mmol) was added to the filtrate,followed by di-tert-butyl dicarbonate (8.4 g, 39 mmol) and the mixturewas stirred at room temperature for 2 h. The reaction mixture was thendiluted with EtOAc (25 mL) and cooled to 0° C. IN HCl (50 mL) was addedslowly. The organic layer was separated, washed with a saturated aq.NaHCO₃ (50 mL) and brine (50 mL), then dried over Na₂SO₄ andconcentrated to give the sub-title compound as a white solid (8.08 g,86%). LCMS calc. for C₁₁H₁₇NNaO₅ (M+Na)⁺: m/z=266.1; found 266.1.

Step 2. 1-tert-Butyl 2-methyl (2S,4R)-4-methyl-5-oxopyrrolidine-1,2-dicarboxylate

This compound is prepared as described by Gu et al, Tetrahedron Lett.,2003, 44, 3203-3205. Lithium hexamethyldisilazide in THF (1.0 M; 8.47mL, 8.47 mmol) was added dropwise over 30 min. to a solution of1-tert-butyl 2-methyl (2S)-5-oxopyrrolidine-1,2-dicarboxylate (2.0 g,8.2 mmol) in THF (20 mL) at −78° C. The resulting mixture was stirred at−78° C. for 1 h. Methyl iodide (1.30 mL, 20.9 mmol) was then addeddropwise over 10 min. After stirring at −78° C. for 2 h, the reactionmixture was allowed to warm to room temperature and stirred for 14 h.The reaction was then quenched by the addition of AcOH (1.00 mL, 17.6mmol), and the reaction mixture was concentrated under reduced pressure.The residue was diluted with EtOAc (100 mL), washed with brine (100 mL),dried over Na₂SO₄, and concentrated under reduced pressure. Theresulting residue was purified by chromatography on silica gel (0-50%EtOAc in hexanes) to give the sub-title compound (0.47 g, 22%). LCMScalc. for C₁₂H₁₉NNaO₅ (M+Na)+: m/z=280.1; found 280.1. ¹H NMR (CDCl₃,400 MHz) δ 4.57 (1H, dd, J=1.6 and 9.6 Hz), 3.77 (3H, s), 2.68 (1H, m),2.27 (1H, m), 1.93 (1H, m), 1.49 (9H, s), 1.21 (3H, d, J=6.8 Hz) ppm.

Step 3. tert-Butyl[(1S,3R)-4-hydroxy-1-(hydroxymethyl)-3-methylbutyl]carbamate

To a solution of 1-tert-butyl 2-methyl(2S,4R)-4-methyl-5-oxopyrrolidine-1,2-dicarboxylate (0.47 g, 1.8 mmol)in THF (4.0 mL) at −10° C., NaBH₄ (0.207 g, 5.48 mmol) was addedfollowed by EtOH (1.0 mL). After stirring at −10° C. for 1 h, themixture was allowed to warm to room temperature and stirred for 15 h.The reaction mixture was then diluted with EtOAc (50 mL), washed withwater (25 mL) and brine (30 mL), then dried over Na₂SO₄ and concentratedunder reduced pressure. The resulting crude product (0.39 g, 92%) wasused directly in the next step without further purification. LCMS calc.for C₁₁H₂₄NO₄ (M+H)⁺: m/z=234.2; found no ionization.

Step 4. tert-Butyl [(3S,5R)-1-benzyl-5-methylpiperidin-3-yl]carbamate

Triethylamine (0.932 mL, 6.69 mmol) was added to a solution oftert-butyl [(1S,3R)-4-hydroxy-1-(hydroxymethyl)-3-methylbutyl]carbamate(0.39 g, 1.7 mmol) in DCM (7.5 mL) at 0° C. Methanesulfonyl chloride(0.388 mL, 5.01 mmol) was then added dropwise to the resulting solution.After stirring at 0° C. for 1 h, the mixture was diluted with DCM (50mL), washed with saturated aq. NaHCO₃ (50 mL), dried over Na₂SO₄ andconcentrated under reduced pressure. Benzylamine (3.65 mL, 33.4 mmol)was added to the resulting residue and mixture was stirred at 70° C. for18 h, then cooled to room temperature. The reaction mixture was dilutedwith EtOAc (100 mL), washed with a 10% aq. K₃PO₄ (50 mL) and brine (50mL), dried over Na₂SO₄, and concentrated under reduced pressure. Theresidue was purified by chromatography on silica gel (0-30% EtOAc inhexanes) to give the title compound as a white solid (0.34 g, 67%). LCMScalc. for C₁₈H₂₉N₂O₂ (M+H)⁺: m/z=305.2; found 305.2.

Step 5. tert-Butyl [(3S,5R)-5-methylpiperidin-3-yl]carbamate

10 wt % Pd on carbon (120 mg, 0.11 mmol) was added to a solution oftert-butyl [(3S,5R)-1-benzyl-5-methylpiperidin-3-yl]carbamate (0.34 g,1.1 mmol) in MeOH (15.0 mL). The mixture was stirred at room temperatureunder a hydrogen atmosphere (1 atm.) for 15 h. The reaction was filteredthrough a pad of diatomaceous earth (eluted with MeOH), and thenconcentrated under reduced pressure. The resulting crude product wasused directly in the next step residue without further purification(0.21 g, 88%). LCMS calc. for C₁₁H₂₃N₂O₂ (M+H)⁺: m/z=215.2; found 215.2.¹H NMR (CDCl₃, 400 MHz) δ 4.33 (1H, m), 3.46 (1H, m), 3.25 (1H, m), 2.94(1H, dd, J=3.6 and 12.8 Hz), 2.18-2.02 (3H, m), 1.60 (1H, m), 1.43 (9H,s), 0.85 (3H, d, J=6.8 Hz) ppm.

Step 6. tert-Butyl [(3S,5R)-5-methyl-1-(5-nitro-2, 3-dihydrofuro[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate

To a microwave vial containing4-iodo-5-nitro-2,3-dihydrofuro[2,3-b]pyridine (from Example 9, step 3)(47.8 mg, 0.164 mmol) and tert-butyl[(3S,5R)-5-methylpiperidin-3-yl]carbamate (33.7 mg, 0.157 mmol), EtOH(1.00 mL) was added, followed by DIPEA (41.5 mg, 0.321 mmol). Themixture was heated under microwave irradiation at 100° C. for 2 h. Aftercooling to room temperature, the reaction mixture was concentrated underreduced pressure. The resulting residue was purified by chromatographyon silica gel (0-100% EtOAc in hexanes) to give the title compound as ayellow solid (44.5 mg, 75%). LCMS calc. for C₁₈H₂₇N₄O₅ (M+H)⁺:m/z=379.2; found 379.2.

Step 7. tert-Butyl [(3S,5R)-1-(5-amino-2, 3-dihydrofuro[2,3-b]pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate

To a solution of tert-butyl[(3S,5R)-5-methyl-1-(5-nitro-2,3-dihydrofuro[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate(44.5 mg, 0.118 mmol) in MeOH (2.00 mL), 10 wt % Pd on carbon (9.3 mg,0.0087 mmol) was added under a nitrogen atmosphere. The mixture was thenhydrogenated (1 atm.) for 4 h. The reaction mixture was then filteredthrough a pad of diatomaceous earth (eluted with MeOH). The filtrate wasconcentrated under reduced pressure to give the crude product as a redsemi-solid (41.0 mg). The crude product was used directly in the nextstep without further purification. LCMS calc. for C₁₈H₂₉N₄O₃ (M+H)⁺:m/z=349.2; found 349.2.

Step 8. 5-Amino-N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

To a mixture of5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylicacid (Example 1, step 6) (47.3 mg, 0.133 mmol), tert-butyl[(3S,5R)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(41.0 mg, 0.118 mmol) and HATU (142.3 mg, 0.3742 mmol), DMF (2.0 mL) wasadded followed by DIPEA (115.8 mg, 0.8960 mmol). The reaction mixturewas stirred at room temperature for 2 h, and then concentrated underreduced pressure. DCM (2.0 mL) was added to the residue followed by TFA(2.0 mL). The mixture was stirred at room temperature for 30 min., andthen concentrated under reduced pressure. The resulting residue waspurified using RP-HPLC (XBridge™ C18 column, eluting with a gradient ofMeCN/water containing 0.1% NH₄OH, at flow rate of 30 mL/min.) to affordthe title compound as a white solid (25.2 mg, 44%). LCMS calc. forC₂₃H₂₅F₂N₆O₂S (M+H)⁺: m/z=487.2; found 487.2.

Example 37N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

Step 1: tert-Butyl[(3R,4R,5S)-4-hydroxy-5-methyl-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate

A mixture containing4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (410 mg, 2.1mmol), tert-butyl [(3R,4R,5S)-4-hydroxy-5-methylpiperidin-3-yl]carbamate(240 mg, 1.0 mmol) and triethylamine (0.5 mL, 4 mmol) in isopropylalcohol (3.0 mL) was stirred at 100° C. for 2 h. The reaction mixturewas concentrated under reduced pressure and the resulting residue waspurified by column chromatography on silica gel using a CombiFlash®apparatus (eluting with 0 to 80% EtOAc in hexanes) to give the sub-titlecompound as pale yellow powder (200 mg, 50%). LCMS calc. for C₁₉H₂₉N₄O₅(M+H)⁺: m/z=393.2. Found: 393.2.

Step 2: tert-Butyl[(3R,4R,5S)-4-hydroxy-5-methyl-1-(3-nitro-1-oxido-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate

mCPBA (0.420 g, 1.87 mmol) was slowly added to a solution of tert-butyl[(3R,4R,5S)-4-hydroxy-5-methyl-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate(0.200 g, 0.510 mmol) in DCM (3.0 mL) at room temperature. The reactionmixture was stirred at room temperature for 1 h. The mixture was thenwashed with aq. Na₂S₂O₃, followed by 1 M NaOH. The organic layer wasseparated, dried and concentrated under reduced pressure. The resultingresidue was further purified by silica gel column chromatography(eluting with 0-30% MeOH in EtOAc) to give the sub-title compound (90mg, 43%) as a light orange powder. LCMS calc. for C₁₉H₂₉N₄O₆ (M+H)⁺:m/z=409.2. Found: 409.2.

Step 3:4-{(3R,4R,5S)-4-(Acetyloxy)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylAcetate

Ac₂O (2.0 mL, 21 mmol) was added to tert-butyl[(3R,4R,5S)-4-hydroxy-5-methyl-1-(3-nitro-1-oxido-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate(0.090 g, 0.22 mmol) in a tube that was then sealed. The reactionmixture was heated in the sealed tube with stirring in an oil bath at90° C. oil bath. The reaction mixture was allowed to cool to roomtemperature and acetyl chloride (0.10 mL) and DIPEA (0.2 mL) were thenadded. The resulting mixture was stirred at room temperature for 15 min.After removal of the solvents under reduced pressure, the resultingresidue was diluted with EtOAc and aq. Na₂CO₃ and stirred at roomtemperature for 30 min. The organic layer was separated, dried andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (eluting with 0-70% EtOAc inhexanes) to give the sub-title compound (86 mg, 79%) as a foamy brownpowder. LCMS calc. for C₂₃H₃₃N₄O₈ (M+1)⁺: m/z=493.2. Found: 493.2.

Step 4:(3R,4R,5S)-1-[7-(Acetyloxy)-3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-4-ylAcetate

A mixture of4-{(3R,4R,5S)-4-(acetyloxy)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl)}-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (0.086 g, 0.17 mmol), water (0.10 mL), AcOH (3.0 mL) and ironpowder (0.200 g, 3.58 mmol) was stirred at room temperature for 3 h. Thereaction mixture was diluted with EtOAc (10 mL), then filtered. Thefiltrate was concentrated under reduced pressure. EtOAc (20 mL) and aq.Na₂CO₃ (10 mL) were added to the residue and the mixture was stirred atroom temperature for 30 min. The organic layer was separated, dried overNa₂SO₄, then filtered and concentrated under reduced pressure to givethe sub-title compound (80 mg, 92%) as a brown foamy powder. LCMS calc.for C₂₃H₃₅N₄O₆ (M+H)⁺: m/z=463.3. Found: 463.3.

Step 5: tert-Butyl{(3R,4R,5S)-1-[3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-4-hydroxy-5-methylpiperidin-3-yl}carbamate

A mixture of(3R,4R,5S)-1-[7-(acetyloxy)-3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-4-ylacetate (11 mg, 0.024 mmol),6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (9.0 mg, 0.036mmol), HATU (33 mg, 0.086 mmol), DMF (0.090 mL) and DIPEA (23 mg, 0.18mmol) was stirred at room temperature for 16 h. The reaction mixture wasdiluted with 1 M NaOH (1.0 mL) and MeOH (1.0 mL) and the mixture wasstirred at room temperature for a further 1 h, and then concentratedunder reduced pressure. After concentrating under reduced pressure, theaqueous layer was extracted with DCM three times. The combined organicextract was dried, filtered and concentrated under reduced pressure togive a crude product, which was further purified by preparative LCMS(pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60mL/min., eluting with a gradient of MeCN and water with 0.15% NH₄OH) togive the sub-title compound as a colorless gum. LCMS calc. forC₃₁H₃₅F₃N₅O₅(M+H)⁺: m/z=614.3. Found: 614.2.

Step 6:N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

A mixture of tert-butyl{(3R,4R,5S)-1-[3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-4-hydroxy-5-methylpiperidin-3-yl}carbamate(6 mg, 0.01 mmol) and TFA in DCM (4.0 M; 2.0 mL, 8.0 mmol) was stirredat room temperature for 1 h. After removal of the solvent, the residuewas then diluted with MeOH (4 mL) and NH₄OH solution (0.5 mL) andfiltered. The filtrate was purified by preparative LCMS (pH=10 method;XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., elutingwith a gradient of MeCN and water with 0.15% NH₄OH) to give twodiastereoisomers of the title compound as a white powders.

Diastereoisomer 1. First peak. Retention time 1.223 min., LCMS calc. forC₂₆H₂₇F₃N₅O₃(M+H)⁺: m/z=514.2; Found: 514.2. ¹H NMR (DMSO-d₆, 500 MHz) δ10.47 (1H, s), 9.31 (1H, s), 8.38 (1H, dd, J=8.5 and 4.0 Hz), 8.20 (1H,dd, J=8.5 and 8.5 Hz), 7.64 (1H, m), 7.29 (2H, dd, J=8.5 and 8.5 Hz),5.24 (1H, d, J=5.0 Hz), 4.84 (1H, m), 4.40 (1H, d, J=4.0 Hz), 3.06 (1H,m), 2.94 (1H, m), 2.85 (2H, m), 2.72 (1H, m), 2.63 (1H, m), 2.58 (1H,m), 2.46 (1H, m), 2.31 (1H, m), 1.80 (1H, m), 1.49 (1H, m), 1.41 (1H,m), 0.71 (3H, d, J=6.5 Hz) ppm.

Diastereoisomer 2. Second peak. Retention time 1.288 min., LCMS calc.for C₂₆H₂₇F₃N₅O₃(M+H)⁺: m/z=514.2. Found: 514.2. ¹H NMR (DMSO-d₆, 500MHz) δ 10.49 (1H, s), 9.31 (1H, s), 8.39 (1H, dd, J=8.5 and 4.0 Hz),8.21 (1H, dd, J=8.5 and 8.5 Hz), 7.65 (1H, m), 7.29 (2H, dd, J=8.5 and8.5 Hz), 5.24 (1H, d, J=5.5 Hz), 4.82 (1H, m), 4.39 (1H, d, J=4.0 Hz),3.06 (1H, m), 2.96 (1H, m), 2.85 (2H, m), 2.72 (1H, m), 2.63 (1H, m),2.59 (1H, m), 2.48 (1H, m), 2.29 (1H, m), 1.82 (1H, m), 1.48 (1H, m),1.41 (1H, m), 0.71 (3H, d, J=6.5 Hz) ppm.

The diastereoisomers correspond to the (7R) and (7S) diastereoisomers ofthe title compound.

Example 383-Amino-N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

To a mixture of3-[(tert-butoxycarbonyl)amino]-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylicacid (16.1 mg, 0.0437 mmol), tert-butyl[(3S,5R)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(14.0 mg, 0.0402 mmol) and HATU (53.1 mg, 0.140 mmol), DMF (1.0 mL) wasadded followed by DIPEA (70.1 μL, 0.402 mmol). The reaction mixture wasstirred at room temperature for 2 h, and then concentrated under reducedpressure. To the resulting residue, DCM (2.0 mL) was added, followed byTFA (2.0 mL). The mixture was stirred at room temperature for 30 min.,and then concentrated under reduced pressure. The resulting residue waspurified using RP-HPLC (XBridge™ C18 column, eluting with a gradient ofMeCN/water containing 0.1% NH₄OH, at flow rate of 30 mL/min.) to affordthe title compound as a white solid (5.9 mg, 29%). LCMS calc. forC₂₅H₂₆F₃N₆O₂(M+H)⁺: m/z=499.2; found 499.2.

Example 39N-{4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

To a mixture of 6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylicacid (13.7 mg, 0.0541 mmol), tert-butyl[(3S,5R)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(15.9 mg, 0.0456 mmol), and HATU (59.1 mg, 0.155 mmol), DMF (1.0 mL) wasadded followed by DIPEA (70.1 μL, 0.402 mmol). The reaction mixture wasstirred at room temperature for 2 h, and then concentrated under reducedpressure. To the resulting residue, DCM (2.0 mL) was added followed byTFA (2.0 mL). The mixture was stirred at room temperature for 30 min.,and then concentrated under reduced pressure. The resulting residue waspurified using RP-HPLC (XBridge™ C18 column, eluting with a gradient ofMeCN/water containing 0.1% NH₄OH, at flow rate of 30 mL/min.) to affordthe title compound as a white solid (8.5 mg, 38%). LCMS calc. forC₂₅H₂₅F₃N₅O₂(M+H)⁺: m/z=484.2; found 484.2.

Example 405-Amino-N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

Step 1. tert-Butyl[(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methyl-1-(5-nitro-2,3-dihydrofuro[2, 3-b]pyridin-4-yl)piperidin-3-yl]carbamate

To a mixture of 4-iodo-5-nitro-2,3-dihydrofuro[2,3-b]pyridine (110.4 mg,0.3780 mmol) and tert-butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(from Example 28, Step 7, 100.0 mg, 0.2902 mmol) was added EtOH (2.0 mL)followed by DIPEA (163.8 mg, 1.267 mmol). The reaction mixture washeated at 100° C. for 15 h, and then concentrated under reducedpressure. The residue was purified by chromatography on silica gel(0-50% EtOAc in hexanes) to afford the sub-title compound as a yellowsolid (118.2 mg, 80%). LCMS calc. for C₂₄H₄₁N₄O₆Si (M+H)⁺: m/z=509.3;found 509.3.

Step 2. tert-Butyl ((3R,4R,5S)-1-(5-amino-2, 3-dihydrofuro[2,3-b]pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate

To a mixture of tert-butyl[(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methyl-1-(5-nitro-2,3-dihydrofuro[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate(73.4 mg, 0.144 mmol), iron powder (89.0 mg, 1.59 mmol), and ammoniumchloride (151.4 mg, 2.830 mmol) was added EtOH (2.0 mL) followed bywater (0.50 mL, 28 mmol). The mixture was stirred at 80° C. for 1 h. Thereaction mixture was filtered through a pad of diatomaceous earth. Thediatomaceous earth pad was eluted with a 10% aqueous solution of K₃PO₄(20 mL), and EtOAc (20 mL). The organic layers were washed with brine(20 mL), dried over Na₂SO₄, and concentrated to give the crude sub-titlecompound (67.8 mg). The crude product was used directly in the next stepwithout further purification. LCMS calc. for C₂₄H₄₃N₄O₄Si (M+H)⁺:m/z=479.3; found 479.3.

Step 3. tert-Butyl[4-({[4-((3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-1-yl)-2,3-dihydrofuro[2,3-b]pyridin-5-yl]amino}carbonyl)-2-(2,6-difluorophenyl)-1,3-thiazol-5-yl]carbamate

To a mixture of tert-butyl((3R,4R,5S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(67.8 mg, 0.142 mmol),5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylicacid (65.4 mg, 0.184 mmol) and HATU (168.1 mg, 0.4421 mmol) was addedDMF (2.0 mL) followed by DIPEA (144.5 mg, 1.118 mmol). The reactionmixture was stirred at room temperature for 3 h, and then concentratedunder reduced pressure. The residue was purified by chromatography onsilica gel (0-50% EtOAc in hexanes) to afford the sub-title compound asa brown solid (29.2 mg, 25%). LCMS calc. for C₃₉H₅₅F₂N₆O₇SSi (M+H)⁺:m/z=817.4; found 817.3.

Step 4.5-Amino-N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

To a solution of tert-butyl[4-({[4-((3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-1-yl)-2,3-dihydrofuro[2,3-b]pyridin-5-yl]amino}carbonyl)-2-(2,6-difluorophenyl)-1,3-thiazol-5-yl]carbamate(29.2 mg, 0.0357 mmol) in MeCN (2.0 mL) was added a 1.7 M dihydrogenhexafluorosilicate solution in water (0.5 mL, 0.8 mmol). The mixture wasstirred at 50° C. for 2 h. After cooling to room temperature, thereaction mixture was neutralized with a 14.8 M NH₄OH solution in water(300 μL, 4.44 mmol), and was purified using RP-HPLC (XBridge™ C18column, eluting with a gradient of MeCN/water containing 0.1% NH₄OH, atflow rate of 30 mL/min.) to afford the title compound as a white solid(6.0 mg, 33%). LCMS calc. for C₂₃H₂₅F₂N₆O₃S (M+H)⁺: m/z=503.2; found503.2.

Example 41N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

Step 1. tert-Butyl{(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-[5-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-2,3-dihydrofuro[2,3-b]pyridin-4-yl]-5-methylpiperidin-3-yl}carbamate

To a mixture of 6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylicacid (13.3 mg, 0.0525 mmol), tert-butyl((3R,4R,5S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(16.7 mg, 0.0349 mmol) and HATU (46.2 mg, 0.122 mmol) was added DMF (2.0mL) followed by DIPEA (70.0 μL, 0.402 mmol). The reaction mixture wasstirred at room temperature for 3 h, and then concentrated under reducedpressure. The residue was purified by chromatography on silica gel(0-100% EtOAc in hexanes) to afford the sub-title compound as a brownsolid (24.9 mg). LCMS calc. for C₃₆H₄₇F₃N₅O₅Si (M+H)⁺: m/z=714.3; found714.3.

Step 2. N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

To a solution of tert-butyl{(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-[5-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-2,3-dihydrofuro[2,3-b]pyridin-4-yl]-5-methylpiperidin-3-yl}carbamate(24.9 mg, 0.0349 mmol) in MeCN (2.0 mL) was added a 1.7 M dihydrogenhexafluorosilicate solution in water (200 μL, 0.340 mmol). The mixturewas stirred at 50° C. for 2 h. After cooling to room temperature, thereaction mixture was neutralized with a 14.8 M NH₄OH solution in water(200 μL, 2.96 mmol), and was purified using RP-HPLC (XBridge™ C18column, eluting with a gradient of MeCN/water containing 0.1% NH₄OH, atflow rate of 30 mL/min.) to afford the title compound as a white solid(2.8 mg, 16%). LCMS calc. for C₂₅H₂₅F₃N₅O₃(M+H)⁺: m/z=500.2; found500.1.

Example 425-Amino-N-{4-[(3S,5R)-3-amino-5-(trifluoromethyl)piperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

Step 1. tert-Butyl [(3S,5R)-1-(5-nitro-2, 3-dihydrofuro[2,3-b]pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate

To a mixture of 4-iodo-5-nitro-2,3-dihydrofuro[2,3-b]pyridine (238.2 mg,0.8157 mmol) and tert-butyl[(3S,5R)-5-(trifluoromethyl)piperidin-3-yl]carbamate (from MolBridge,203.9 mg, 0.7600 mmol) was added EtOH (3.0 mL), followed by DIPEA (539.5mg, 4.174 mmol). The mixture was stirred at 120° C. for 18 h. Aftercooling to room temperature, the reaction was concentrated under reducedpressure. The residue was purified by chromatography on silica gel(0-50% EtOAc in hexanes) to afford the sub-title compound as a yellowsolid (227.1 mg, 69%). LCMS calc. for C₁₈H₂₄F₃N₄O₅(M+H)⁺: m/z=433.2;found 433.2.

Step 2. tert-Butyl [(3S,5R)-1-(5-amino-2, 3-dihydrofuro[2,3-b]pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate

To a mixture of tert-butyl[(3S,5R)-1-(5-nitro-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate(227.1 mg, 0.5252 mmol), iron powder (289.6 mg, 5.186 mmol) and ammoniumchloride (462.4 mg, 8.644 mmol) was added EtOH (5.0 mL) followed bywater (2.5 mL). The mixture was stirred at 80° C. for 1 h. The reactionmixture was filtered through a pad of diatomaceous earth. Thediatomaceous earth pad was eluted with a 10% aqueous solution of K₃PO₄(50 mL), and EtOAc (50 mL). The separated organic layer was washed withbrine (50 mL), dried over Na₂SO₄, and concentrated to give the crudesub-title compound (211.5 mg). The crude product was used directly inthe next step without further purification. LCMS calc. forC₁₈H₂₆F₃N₄O₃(M+H)⁺: m/z=403.2; found 403.2.

Step 3.5-Amino-N-{4-[(3S,5R)-3-amino-5-(trifluoromethyl)piperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

To a mixture of5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylicacid (58.2 mg, 0.163 mmol), tert-butyl[(3S,5R)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate(55.3 mg, 0.137 mmol) and HATU (180.9 mg, 0.4758 mmol) was added DMF(2.0 mL) followed by DIPEA (162.2 mg, 1.255 mmol). The reaction mixturewas stirred at room temperature for 3 h, and then concentrated underreduced pressure. To the resulting residue was added DCM (2.0 mL),followed by TFA (2.0 mL). The mixture was stirred at room temperaturefor 30 min., and then concentrated under reduced pressure. The resultingresidue was purified using RP-HPLC (XBridge™ C18 column, eluting with agradient of MeCN/water containing 0.1% NH₄OH, at flow rate of 30mL/min.) to afford the title compound as a white solid (9.7 mg, 13%).LCMS calc. for C₂₃H₂₂F₅N₆O₂S (M+H)⁺: m/z=541.1; found 541.1.

Example 43N-{4-[(3S,5R)-3-amino-5-(trifluoromethyl)piperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

To a mixture of 6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylicacid (38.7 mg, 0.153 mmol), tert-butyl[(3S,5R)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate(51.4 mg, 0.128 mmol) and HATU (178.7 mg, 0.4700 mmol) was added DMF(2.0 mL) followed by DIPEA (159.5 mg, 1.234 mmol). The reaction mixturewas stirred at room temperature for 3 h, and then concentrated underreduced pressure. To the resulting residue was added DCM (2.0 mL),followed by TFA (2.0 mL). The mixture was stirred at room temperaturefor 30 min., and then concentrated under reduced pressure. The resultingresidue was purified using RP-HPLC (XBridge™ C18 column, eluting with agradient of MeCN/water containing 0.1% NH₄OH, at flow rate of 30mL/min.) to afford the title compound as a white solid (13.5 mg, 20%).LCMS calc. for C₂₅H₂₂F₆N₅O₂(M+H)⁺: m/z=538.2; found 538.2.

Example 445-Amino-N-{4-[(3S,5R)-3-amino-5-(trifluoromethyl)piperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

Step 1. tert-Butyl[(3S,5R)-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate

To a mixture of 4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine(144.2 mg, 0.7260 mmol) and tert-butyl[(3S,5R)-5-(trifluoromethyl)piperidin-3-yl]carbamate (from MolBridge,179.9 mg, 0.6706 mmol) was added 1-butanol (3.0 mL) followed by DIPEA(493.7 mg, 3.820 mmol). The mixture was stirred at 150° C. for 6 h.After cooling to room temperature, the reaction mixture was concentratedunder reduced pressure. The residue was purified by chromatography onsilica gel (0-50% EtOAc in hexanes) to afford the sub-title compound asa pale yellow solid (179.2 mg, 62%). LCMS calc. for C₁₉H₂₆F₃N₄O₄(M+H)⁺:m/z=431.2; found 431.2.

Step 2. tert-Butyl[(3S,5R)-1-(3-nitro-1-oxido-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate

To a mixture of tert-butyl[(3S,5R)-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate(179.2 mg, 0.4163 mmol) and mCPBA (210.6 mg, 0.9397 mmol) was added DCM(2.00 mL). The reaction mixture was stirred at room temperature for 13h. The mixture was diluted with DCM (30 mL), washed with 1 M NaOHaqueous solution. The separated aqueous layer was extracted with DCM(3×30 mL). The combined organic layers were washed with brine (100 mL),dried over Na₂SO₄, and concentrated under reduced pressure. Theresulting residue was purified by chromatography on silica gel (0-30%MeOH in DCM) to give the sub-title compound (114.7 mg, 62%). LCMS calc.for C₁₉H₂₆F₃N₄O₅(M+H)⁺: m/z=447.2; found 447.2.

Step 3.4-[(3S,5R)-3-[(tert-Butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylAcetate

To tert-butyl[(3S,5R)-1-(3-nitro-1-oxido-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate(114.7 mg, 0.2569 mmol) was added Ac₂O (2.0 mL, 21 mmol). The reactionmixture was heated at 90° C. for 1 h. After cooling to room temperature,the reaction mixture was concentrated under reduced pressure. Theresidue was diluted with DCM, and poured into a saturated aqueoussolution of Na₂CO₃ at 0° C. The separated aqueous layer was furtherextracted with DCM (3 times). The combined organic layers were washedwith brine, dried over Na₂SO₄, and concentrated under reduced pressure.The resulting residue was purified by chromatography on silica gel(0-100% EtOAc in hexanes) to give the sub-title compound as a brownfoamy solid (92.3 mg, 74%). LCMS calc. for C₂₁H₂₈F₃N₄O₆(M+H)⁺:m/z=489.2; found 489.2.

Step 4.3-Amino-4-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylAcetate

To a mixture of4-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (92.3 mg, 0.189 mmol) and iron powder (295.6 mg, 5.293 mmol) wasadded AcOH (2.0 mL). The mixture was stirred at room temperature for 3h. The reaction mixture was diluted with EtOAc, filtered through a padof diatomaceous earth (eluted with EtOAc). The filtrate was washed witha saturated aqueous solution of Na₂CO₃, dried over Na₂SO₄, andconcentrated to give the crude sub-title compound as dark semi-solid(86.6 mg). The crude product was used directly in the next step withoutfurther purification. LCMS calc. for C₂₁H₃₀F₃N₄O₄(M+H)⁺: m/z=459.2;found 459.2.

Step 5.3-({[5-[(tert-Butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-4-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylAcetate

To a mixture of3-amino-4-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (86.6 mg, 0.189 mmol),5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylicacid (89.5 mg, 0.251 mmol), and HATU (221.8 mg, 0.5833 mmol) was addedDMF (2.0 mL) followed by DIPEA (164.3 mg, 1.271 mmol). The reactionmixture was stirred at 45° C. for 14 h, and then concentrated underreduced pressure. The resulting residue was purified by chromatographyon silica gel (0-100% EtOAc in hexanes) to give the sub-title compoundas a dark semi-oil (110.3 mg, 73%). LCMS calc. for C₃₆H₄₂F₅N₆O₇S (M+H)⁺:m/z=797.3; found 797.3.

Step 6.5-Amino-N-{4-[(3S,5R)-3-amino-5-(trifluoromethyl)piperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

To a solution of3-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-4-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (110.3 mg, 0.1384 mmol) in THF (1.0 mL) was added a 1.0 M NaOHsolution in water (1.00 mL, 1.00 mmol) followed by MeOH (2.0 mL). Thereaction mixture was stirred at room temperature for 1 h, and thenconcentrated under reduced pressure. To the resulting residue was addedDCM (2.0 mL), followed by TFA (2.0 mL). The mixture was stirred at roomtemperature for 30 min., and then concentrated under reduced pressure.The resulting residue was purified using RP-HPLC (XBridge™ C18 column,eluting with a gradient of MeCN/water containing 0.1% NH₄OH, at flowrate of 30 mL/min.) to afford both diastereoisomers of the titlecompound as white solids (9.3 mg for each, total yield 24%).

Diastereoisomer 1. First peak. Retention time 2.044 min., LCMS calc. forC₂₄H₂₄F₅N₆O₂S (M+H)⁺: m/z=555.2; found 555.0.

Diastereoisomer 2. Second peak. Retention time 2.163 min., LCMS calc.for C₂₄H₂₄F₅N₆O₂S (M+H)⁺: m/z=555.2; found 555.0.

The diastereoisomers correspond to the (7R) and (7S) diastereoisomers ofthe title compound.

Example 45N-{4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

Step 1: tert-Butyl[(3S,5R)-5-methyl-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate

A mixture of 4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (19.4mg, 0.10 mmol), tert-butyl [(3S,5R)-5-methylpiperidin-3-yl]carbamate(22.0 mg, 0.10 mmol) and triethylamine (40.9 μL, 0.29 mmol) in isopropylalcohol (0.224 mL) was stirred at 100° C. for 40 min. The reactionmixture was concentrated under vacuum and the residue was purified bysilica gel column chromatography using CombiFlash® (0 to 50% EtOAc inhexanes) to give the sub-title compound as pale yellow powder (36.8 mg,100%). LCMS calc. for C₁₉H₂₉N₄O₄ (M+H)⁺: m/z=377.1. Found: 377.1.

Step 2: tert-Butyl[(3S,5R)-5-methyl-1-(3-nitro-1-oxido-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate

To a solution of tert-butyl[(3S,5R)-5-methyl-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate(32.3 mg, 0.086 mmol) in DCM (0.50 mL) at 0° C. was added mCPBA (25.0mg, 0.112 mmol). The reaction mixture was stirred at room temperaturefor 1 h. The mixture was treated with Na₂S₂O₃ solution, followed by 1NNaOH, and stirred for 30 min. at room temperature. The organic layer wasseparated, dried, filtered and concentrated under vacuum to give thecrude N-oxide product. The crude product was purified by preparativeLC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min.,eluting with a gradient of MeCN and water with 0.1% NH₄OH) to afford thesub-title compound (20 mg, 40%). LCMS calc. for C₁₉H₂₉N₄O₅ (M+H)⁺:m/z=393.2. Found: 393.1.

Step 3:4-{(3S,5R)-3-[(tert-Butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylAcetate

Ac₂O (15.6 mg, 0.153 mmol) was added to the N-oxide tert-butyl[(3S,5R)-5-methyl-1-(3-nitro-1-oxido-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate(10.0 mg, 0.026 mmol) in a sealed tube. The reaction mixture was heatedat 90° C. for 30 min. and the solution was then concentrated underreduced pressure. The residue was then dissolved in DCM, then pouredinto ice cold Na₂CO₃ solution. The aqueous layer was extracted with DCMtwice. The combined organic layers were dried, filtered and concentratedunder reduced pressure to give the sub-title compound as off-whitepowder (11.2 mg, 95%). LCMS calc. for C₂₁H₃₁N₄O₆ (M+H)⁺: m/z=435.2.Found: 435.1.

Step 4:3-Amino-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylAcetate

A mixture of4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (11.2 mg, 0.026 mmol), AcOH (73.3 μL) and iron powder (14.4 mg,0.26 mmol) was stirred at room temperature for 3 h. The reaction mixturewas diluted with EtOAc, filtered and washed with more EtOAc. Thefiltrate was concentrated under vacuum, and the residue was diluted withEtOAc and neutralized with Na₂CO₃ solution. The mixture was stirred atroom temperature for 30 min. The organic layer was separated, dried overNa₂SO₄, filtered and concentrated under vacuum to give the sub-titlecompound as a yellowish solid (10.0 mg, 96%). LCMS calc. for C₂₁H₃₃N₄O₄(M+H)⁺: m/z=405.2. Found: 405.1.

Step 5:4-{(3S,5R)-3-[(tert-Butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylAcetate

A mixture of3-amino-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (12.0 mg, 0.030 mmol),6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (9.0 mg, 0.036mmol), HATU (28.2 mg, 0.074 mmol) in DMF (0.07 mL) and DIPEA (11.5 mg,0.089 mmol) was stirred at room temperature for 2 h. The reactionmixture was filtered, concentrated and purified by preparative LC-MS(XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min.,eluting with a gradient of MeCN and water with 0.1% NH₄OH) to afford thesub-title compound (11 mg, 58%). LCMS calc. for C₃₃H₃₇F₃N₅O₅(M+H)⁺:m/z=640.3. Found: 640.1.

Step 6:N-{4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

A mixture of4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (10.2 mg, 0.0159 mmol), MeOH (0.2 mL), THF (0.1 mL) and 1.0 Maq. NaOH (0.10 mL, 0.10 mmol) was stirred at room temperature for 30min., then evaporated under reduced pressure.

The resulting crude intermediate was dissolved in DCM (0.2 mL), and TFA(0.16 mL, 2.1 mmol) was added. The reaction mixture was stirred at roomtemperature for 30 min. The solvent was removed under reduced pressure.The residue was diluted with 4 mL of MeOH, filtered and purified bypreparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm,60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH₄OH)to give both diastereoisomers of the title compound as white powders. Onanalytical HPLC (Waters SunFire™ C18, 2.1×50 mm, 5 μm; flow rate 3mL/min.; injection volume 2 μL; gradient from 2 to 80% B in 3 minutes(A=water with 0.025% TFA, B=MeCN)) the diastereoisomers had thefollowing properties:

Diastereoisomer 1. First peak. Retention time 1.805 min., LCMS calc. forC₂₆H₂₇F₃N₅O₂ (M+H)⁺: m/z=498.2. Found: 498.1.

Diastereoisomer 2. Second peak. Retention time 1.942 min., LCMS calc.for C₂₆H₂₇F₃N₅O₂ (M+H)⁺: m/z=498.2. Found: 498.1.

Example 463-Amino-N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

Step 1:3-({[3-[(tert-Butoxycarbonyl)amino]-6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylAcetate

A mixture of3-amino-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (13.0 mg, 0.032 mmol),3-[(tert-butoxycarbonyl)amino]-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylicacid (14.2 mg, 0.039 mmol), HATU (30.5 mg, 0.080 mmol) in DMF (0.09 mL)and DIPEA (0.019 mL, 0.096 mmol) was stirred at room temperature for 16h. The reaction mixture was diluted with MeOH and purified bypreparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm,60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH₄OH)to give the sub-title compound as a white powder (14.2 mg, 59%). LCMScalc. for C₃₈H₄₆F₃N₆O₇(M+H)⁺: m/z=755.3. Found: 755.1.

Step 2:3-Amino-N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

A mixture of3-({[3-[(tert-butoxycarbonyl)amino]-6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (14.2 mg, 0.019 mmol), MeOH (0.22 mL), THF (0.12 mL) and 1.0 Maq. NaOH (0.12 mL, 0.12 mmol) was stirred at room temperature for 20min. The solvent was then evaporated under reduced pressure.

The crude intermediate was dissolved in DCM (0.19 mL), and TFA (0.19 mL,2.5 mmol) was added. The reaction mixture was stirred at roomtemperature for 20 min. then evaporated under reduced pressure. Theresidue was diluted with MeOH, filtered and purified by preparativeLC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min.,eluting with a gradient of MeCN and water with 0.1% NH₄OH) to give bothdiastereoisomers of the title compound as white powders. On analyticalHPLC (Waters SunFire™ C18, 2.1×50 mm, 5 μm; Flow rate 3 mL/min.;injection volume 2 μL; gradient from 2 to 80% B in 3 minutes (A=waterwith 0.025% TFA, B=MeCN)) the diastereoisomers had the followingproperties:

Diastereoisomer 1. First peak. Retention time 1.775 min., LCMS calc. forC₂₆H₂₈F₃N₆O₂(M+H)⁺: m/z=513.2. Found: 513.1.

Diastereoisomer 2. Second peak. Retention time 1.853 min., LCMS calc.for C₂₆H₂₈F₃N₆O₂(M+H)⁺: m/z=513.2. Found: 513.1.

The diastereoisomers correspond to the (7R) and (7S) diastereoisomers ofthe title compound.

Example 475-Amino-N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

Step 1:3-({[5-[(tert-Butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylAcetate

A mixture of3-amino-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (13.0 mg, 0.032 mmol),5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylicacid (13.7 mg, 0.040 mmol), HATU (30.5 mg, 0.080 mmol) in DMF (0.09 mL)and DIPEA (12.5 mg, 0.096 mmol) was stirred at room temperature for 16h. The reaction mixture was diluted with MeOH and purified bypreparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm,60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH₄OH)to give the sub-title compound as a white powder (12.4 mg, 52%). LCMScalc. for C₃₆H₄₅F₂N₆O₇S (M+H)⁺: m/z=743.3. Found: 743.3.

Step 2:5-Amino-N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

A mixture of3-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (12.4 mg, 0.0167 mmol), MeOH (0.2 mL), THF (0.1 mL) and 1.0 Maq. NaOH (0.11 mL, 0.11 mmol) was stirred at room temperature for 20min. The organic solvents and water were removed under reduced pressureto give a crude intermediate, which was dissolved in DCM (0.2 mL),followed by the addition of TFA (0.17 mL, 2.2 mmol). The reactionmixture was stirred at room temperature for 20 min. After removal of thesolvent under reduced pressure, the residue was diluted with MeOH,filtered and purified by preparative LC-MS (XBridge™ preparative C18 5μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCNand water with 0.1% NH₄OH) to give both diastereoisomers of the titlecompound as white powders. On analytical HPLC (Waters SunFire™ C18,2.1×50 mm, 5 μm; Flow rate 3 mL/min.; injection volume 2 μL; gradientfrom 2 to 80% B in 3 minutes (A=water with 0.025% TFA, B=MeCN)) thediastereoisomers had the following properties:

Diastereoisomer 1. First peak. Retention time 1.693 min., LCMS calc. forC₂₄H₂₇F₂N₆O₂S (M+H)⁺: m/z=501.2. Found: 501.1.

Diastereoisomer 2. Second peak. Retention time 1.824 min., LCMS calc.for C₂₄H₂₇F₂N₆O₂S (M+H)⁺: m/z=501.2. Found: 501.1.

The diastereoisomers correspond to the (7R) and (7S) diastereoisomers ofthe title compound.

Example 483-Amino-N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

Step 1: tert-Butyl{(3R,4R,5S)-1-[3-({[3-[(tert-butoxycarbonyl)amino]-6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-4-hydroxy-5-methylpiperidin-3-yl}carbamate

A mixture of(3R,4R,5S)-1-[7-(acetyloxy)-3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-4-ylacetate (11.0 mg, 0.024 mmol),3-[(tert-butoxycarbonyl)amino]-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylicacid (12 mg, 0.03 mmol), HATU (33 mg, 0.09 mmol) in DMF (0.09 mL) andDIPEA (23 mg, 0.18 mmol) was stirred at room temperature for 16 h. Thereaction mixture was diluted with 1N NaOH solution (0.5 mL) and MeOH(0.5 mL). The reaction mixture was stirred at room temperature for 1 h.After concentration under vacuum, the aqueous layer was extracted withDCM three times. The combined organic layers were dried, filtered andconcentrated under reduced pressure to give the crude product, which waspurified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and waterwith 0.1% NH₄OH) to give the sub-title compound as a white powder. LCMScalc. for C₃₆H₄₄F₃N₆O₇(M+H)⁺: m/z=729.3; Found: 729.4.

Step 2:3-Amino-N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

A mixture of tert-butyl{(3R,4R,5S)-1-[3-({[3-[(tert-butoxycarbonyl)amino]-6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-4-hydroxy-5-methylpiperidin-3-yl}carbamate(7.0 mg, 0.01 mmol) and 4.0 M TFA in DCM (2.0 mL) was stirred at roomtemperature for 1 h. After removal of the solvent under reducedpressure, the residue was diluted with MeOH, filtered and purified bypreparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm,60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH₄OH)to give both diastereoisomers of the title compound as white powders. Onanalytical HPLC (Waters SunFire™ C18, 2.1×50 mm, 5 μm; flow rate 3mL/min.; injection volume 2 μL; gradient from 2 to 80% B in 3 minutes(A=water with 0.025% TFA, B=MeCN)), the diastereoisomers had thefollowing properties:

Diastereoisomer 1. First peak. Retention time 1.450 min., LCMS calc. forC₂₆H₂₈F₃N₆O₃(M+H)⁺: m/z=529.2. Found: 529.2.

Diastereoisomer 2. Second peak. Retention time 1.506 min., LCMS calc.for C₂₆H₂₈F₃N₆O₃(M+H)⁺: m/z=529.2. Found: 529.2.

The diastereoisomers correspond to the (7R) and (7S) diastereoisomers ofthe title compound.

Example 495-Amino-N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

Step 1: tert-Butyl{(3R,4R,5S)-1-[3-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-4-hydroxy-5-methylpiperidin-3-yl}carbamate

A mixture of(3R,4R,5S)-1-[7-(acetyloxy)-3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-4-ylacetate (11.0 mg, 0.024 mmol),5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylicacid (12 mg, 0.032 mmol), HATU (33 mg, 0.09 mmol) in DMF (0.09 mL) andDIPEA (23 mg, 0.18 mmol) was stirred at room temperature for 16 h. Thereaction mixture was diluted with 1 M NaOH solution (0.5 mL) and MeOH(0.5 mL). The reaction mixture was stirred at room temperature for 1 h,and was then concentrated under reduced pressure. The resulting aqueouslayer was extracted with DCM three times. The combined organic layerswere dried, filtered and concentrated under reduced pressure to give thecrude product, which was purified by preparative LC-MS (XBridge™preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with agradient of MeCN and water with 0.1% NH₄OH) to give the sub-titlecompound as a white powder. LCMS calc. for C₃₄H₄₃F₂N₆O₇S (M+H)⁺:m/z=717.3. Found: 717.3.

Step 2:5-Amino-N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

A mixture of tert-butyl{(3R,4R,5S)-1-[3-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-4-hydroxy-5-methylpiperidin-3-yl}carbamate(7.0 mg, 0.01 mmol) and 4.0 M TFA in DCM (2.0 mL) was stirred at roomtemperature for 1 h. After removal of the solvent under reducedpressure, the residue was diluted with MeOH, filtered and purified bypreparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm,60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH₄OH)to give both diastereoisomers of the title compound as white powders. Onanalytical HPLC (Waters SunFire™ C18, 2.1×50 mm, 5 μm; flow rate 3mL/min.; injection volume 2 μL; gradient from 2 to 80% B in 3 minutes(A=water with 0.025% TFA, B=MeCN)), the diastereoisomers had thefollowing properties:

Diastereoisomer 1. First peak. Retention time 1.325 min., LCMS calc. forC₂₄H₂₇F₂N₆O₃S (M+H)⁺: m/z=517.2. Found: 517.2.

Diastereoisomer 2. Second peak. Retention time 1.378 min., LCMS calc.for C₂₄H₂₇F₂N₆O₃S (M+H)⁺: m/z=517.2. Found: 517.2.

The diastereoisomers correspond to the (7R) and (7S) diastereoisomers ofthe title compound.

Example 50N-{4-[(3S)-3-Aminopiperidin-1-yl]-7-oxo-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

Step 1: tert-Butyl{(3S)-1-[3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]piperidin-3-yl}carbamate

A mixture of4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl)}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (174 mg, 0.28 mmol), MeOH (0.7 mL), THF (0.7 mL) and 1.0 M aq.NaOH (1.1 mL, 1.1 mmol) was stirred at room temperature for 20 min. Theorganic solvents were removed under reduced pressure. The aqueous layerwas diluted with EtOAc and NH₄Cl (aq.), extracted with EtOAc twice. Thecombined organic layers were dried, filtered and concentrated underreduced pressure to give the sub-title compound (151 mg, 93%). LCMScalc. for C₃₀H₃₃F₃N₅O₄(M+H)⁺: m/z=584.2. Found: 584.2.

Step 2: tert-Butyl{(3S)-1-[3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-7-oxo-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]piperidin-3-yl}carbamate

To a solution of tert-butyl{(3S)-1-[3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]piperidin-3-yl}carbamate(100 mg, 0.17 mmol) in DCM (0.8 mL), Dess-Martin periodinane (95 mg,0.22 mmol) was slowly added. The reaction mixture was stirred at roomtemperature for 40 min. The reaction mixture was neutralized with 1 MNaOH, diluted with MeOH, filtered and concentrated under vacuum. Thecrude product was purified by silica gel column chromatography usingCombiFlash® (0 to 100% EtOAc in hexanes) to give light brown powder asthe sub-title compound (41 mg, 41%). LCMS calc. for C₃₀H₃₁F₃N₅O₄(M+H)⁺:m/z=582.2. Found: 582.2.

Step 3:N-{4-[(3S)-3-Aminopiperidin-1-yl]-7-oxo-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

A mixture of tert-butyl{(3S)-1-[3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-7-oxo-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]piperidin-3-yl}carbamate(6.0 mg, 0.010 mmol) in DCM (0.05 mL) and TFA (0.052 mL, 0.68 mmol) wasstirred at room temperature for 20 min. The solution was thenconcentrated under reduced pressure. The residue was diluted with MeOH,filtered and purified by preparative LC-MS (XBridge™ preparative C18 5μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCNand water with 0.1% NH₄OH) to give the title compound as a white powder(2.2 mg, 44%). LCMS calc. for C₂₅H₂₃F₃N₅O₂(M+H)⁺: m/z=482.2; Found:482.3.

Example 51N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(4-ethoxy-2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

Step 1: 6-(4-Ethoxy-2, 6-difluorophenyl)-5-fluoropyridine-2-carboxylicacid

A mixture of (4-ethoxy-2,6-difluorophenyl)boronic acid (0.11 g, 0.54mmol), methyl 6-bromo-5-fluoropyridine-2-carboxylate (0.14 g, 0.60mmol), 1,4-dioxane (1.3 mL), DIPEA (0.19 mL, 1.1 mmol) and water (0.03mL) was flushed with nitrogen for 5 min. and thenbis(tri-tert-butylphosphine)palladium (0.056 g, 0.11 mmol) was added.The reaction mixture was heated at 130° C. for 2 h. The mixture wasfiltered and concentrated under vacuum, and the residue was purified bysilica gel column chromatography using CombiFlash® (0-50% EtOAc inhexanes) to give the desired ester (0.27 g, 60%). This ester wasdissolved in THF (1.0 mL) and MeOH (1.0 mL), followed by the addition of1.0 M aq. NaOH (2.0 mL, 2.0 mmol). The reaction mixture was stirred atroom temperature for 1 h, After removal of the organic solvent underreduced pressure, the residue was neutralized with HCl. The aqueouslayer was extracted with EtOAc twice. The combined organic layers weredried over Na₂SO₄, filtered and concentrated under vacuum to give thesub-title compound. LCMS calc. for C₁₄H₁₁F₃NO₃ (M+H)⁺: m/z=298.1. Found:298.1.

Step 2: tert-Butyl {(3R,4R,5S)-1-[3-({[6-(4-ethoxy-2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-4-hydroxy-5-methylpiperidin-3-yl}carbamate

A mixture of(3R,4R,5S)-1-[7-(acetyloxy)-3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-4-ylacetate (12.4 mg, 0.027 mmol),6-(4-ethoxy-2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (8.0mg, 0.027 mmol), HATU (37 mg, 0.098 mmol) in DMF (0.1 mL) and DIPEA (26mg, 0.20 mmol) was stirred at room temperature for 16 h. The reactionmixture was diluted with 1 M NaOH solution (0.5 mL) and MeOH (0.5 mL).The reaction mixture was stirred at room temperature for 1 h. Afterconcentration under reduced pressure, the aqueous layer was extractedwith DCM three times. The combined organic layers were dried, filteredand concentrated under vacuum to give the crude product, which waspurified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and waterwith 0.1% NH₄OH) to give the sub-title compound as a white powder. LCMScalc. for C₃₃H₃₉F₃N₅O₆(M+H)⁺: m/z=658.3. Found: 658.3.

Step 3:N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(4-ethoxy-2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

A mixture of tert-butyl{(3R,4R,5S)-1-[3-({[6-(4-ethoxy-2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-4-hydroxy-5-methylpiperidin-3-yl}carbamate(6 mg, 0.01 mmol) and 4.0 M TFA in DCM (2.0 mL) was stirred at roomtemperature for 1 h. After removal of the solvent under reducedpressure, the residue was diluted with MeOH, filtered and purified bypreparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm,60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH₄OH)to give both diastereoisomers as white powders. On analytical HPLC(Waters SunFire™ C18, 2.1×50 mm, 5 μm; flow rate 3 mL/min.; injectionvolume 2 μL; gradient from 2 to 80% B in 3 minutes (A=water with 0.025%TFA, B=MeCN)), the diastereoisomers had the following properties:

Diastereoisomer 1. First peak. Retention time 1.551 min., LCMS calc. forC₂₈H₃₁F₃N₅O₄(M+H)⁺: m/z=558.2. Found: 558.2.

Diastereoisomer 2. Second peak. Retention time 1.608 min., LCMS calc.for C₂₈H₃₁F₃N₅O₄(M+H)⁺: m/z=558.2. Found: 558.2.

The diastereoisomers correspond to the (7R) and (7S) diastereoisomers ofthe title compound.

Example 52N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

Step 1: tert-Butyl{(3R,4R,5S)-1-[3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-4-hydroxy-5-methylpiperidin-3-yl}carbamate

A mixture of tert-butyl[(3R,4R,5S)-1-(3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-4-hydroxy-5-methylpiperidin-3-yl]carbamate(6.0 mg, 0.017 mmol),6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (5.0 mg, 0.02mmol), HATU (15.7 mg, 0.041 mmol) in DMF (0.05 mL) and DIPEA (0.01 mL,0.05 mmol) was stirred at room temperature for 1 h. The reaction mixturewas diluted with EtOAc and Na₂CO₃ (aq.). The aqueous layer was extractedwith EtOAc twice. The combined organic layers were dried, filtered andconcentrated under vacuum. The resulting crude product was used directlyin the next step. LCMS calc. for C₃₁H₃₅F₃N₅O₄(M+H)⁺: m/z=598.3. Found:598.2.

Step 2:N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

A mixture of tert-butyl{(3R,4R,5S)-1-[3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-4-hydroxy-5-methylpiperidin-3-yl}carbamate(6.0 mg, 0.010 mmol), DCM (0.09 mL) and TFA (0.085 mL, 1.1 mmol) wasstirred at room temperature for 20 min. After concentration, the residuewas diluted with MeOH, filtered and purified by preparative LC-MS(XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min.,eluting with a gradient of MeCN and water with 0.1% NH₄OH) to give thetitle compound as a white powder (4.6 mg, 92%). LCMS calc. forC₂₆H₂₇F₃N₅O₂(M+H)⁺: m/z=498.2. Found: 498.3.

Example 535-Amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluoro-3-methoxyphenyl)-1,3-thiazole-4-carboxamide

Step 1. Methyl5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluoro-3-methoxyphenyl)-1,3-thiazole-4-carboxylate

To a vial, methyl2-bromo-5-[(tert-butoxycarbonyl)amino]-1,3-thiazole-4-carboxylate (fromExample 1 step 3, 104 mg, 0.309 mmol),(2,6-difluoro-3-methoxyphenyl)boronic acid (from Aldrich, 207 mg, 1.10mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (37.5 mg, 0.0477 mmol), and potassium phosphate (276 mg, 1.30mmol) were added. The vial was sealed with a PTFE screw-cap then purgedwith nitrogen three times. 1,4-Dioxane (4.0 mL) was added, followed bydeoxygenated water (2.0 mL). The mixture was heated at 40° C. for 1 h.The reaction mixture was allowed to cool to room temperature. Additional(2,6-difluoro-3-methoxyphenyl)boronic acid (262 mg, 1.39 mmol) anddicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (40.2 mg, 0.0511 mmol) were added. The mixture was stirred at roomtemperature for 15 h. The mixture was filtered through a pad ofdiatomaceous earth (eluted with EtOAc) and concentrated. The residue waspurified on silica gel (eluting with 0-50% EtOAc in hexanes) to give thesub-title compound as a white solid (48.5 mg, 39%). LCMS calc. forC₁₇H₁₉F₂N₂O₅S (M+H)⁺: m/z=401.1; Found: 401.1.

Step 2.5-[(tert-Butoxycarbonyl)amino]-2-(2,6-difluoro-3-methoxyphenyl)-1,3-thiazole-4-carboxylicacid

To a mixture of methyl5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluoro-3-methoxyphenyl)-1,3-thiazole-4-carboxylate(48.5 mg, 0.121 mmol) and lithium hydroxide, monohydrate (37 mg, 0.89mmol) was added MeOH (1.5 mL), followed by water (1.5 mL). The reactionmixture was stirred at 60° C. for 3.5 h. The reaction mixture wasallowed to cool to room temperature and 4.0 M hydrogen chloride in water(0.25 mL, 0.99 mmol) was added to adjust the pH to 1-2. The mixture wasdiluted with EtOAc (50 mL) and brine (50 mL). The aqueous layer wasfurther extracted with EtOAc (2×50 mL). The combined organic extractswere dried over Na₂SO₄ and concentrated under reduced pressure to givethe sub-title compound as a white solid which was used directly in thenext step without further purification (52.2 mg). LCMS calc. forC₁₆H₁₇F₂N₂O₅S (M+H)⁺: m/z=387.1. Found: 387.1.

Step 3:3-({[5-[(tert-Butoxycarbonyl)amino]-2-(2,6-difluoro-3-methoxyphenyl)-1,3-thiazol-4-yl]carbonyl}amino)-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylAcetate

A mixture of3-amino-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (10.0 mg, 0.0256 mmol),5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluoro-3-methoxyphenyl)-1,3-thiazole-4-carboxylicacid (9.9 mg, 0.026 mmol) and HATU (24.3 mg, 0.064 mmol) in DMF (0.06mL) and DIPEA (0.014 mL, 0.077 mmol) was stirred at room temperature for4 h. The mixture was diluted with MeOH and purified by preparative LC-MS(XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min.,eluting with a gradient of MeCN and water with 0.1% NH₄OH) to give thesub-title compound as a white powder (3.2 mg, 16%). LCMS calc. forC₃₆H₄₅F₂N₆O₈S (M+H)⁺: m/z=759.3. Found: 759.3.

Step 4:5-Amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluoro-3-methoxyphenyl)-1,3-thiazole-4-carboxamide

A mixture of3-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluoro-3-methoxyphenyl)-1,3-thiazol-4-yl]carbonyl}amino)-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (3.2 mg, 0.0042 mmol), MeOH (50 μL), THF (25 μL) and 1.0 M aq.NaOH (27 μL, 0.027 mmol) was stirred at room temperature for 20 min. Theorganic solvents were removed under reduced pressure to give a crudeintermediate, which was dissolved in DCM (0.04 mL), and then TFA (0.043mL, 0.56 mmol) was added. The reaction mixture was stirred at roomtemperature for 20 min. After concentration under reduced pressure, theresidue was diluted with MeOH, filtered and purified by preparativeLC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min.,eluting with a gradient of MeCN and water with 0.1% NH₄OH) to give bothdiastereoisomers of the title compound as white powders. On analyticalHPLC (Waters SunFire™ C18, 2.1×50 mm, 5 μm; flow rate 3 mL/min.;injection volume 2 μL; gradient from 2 to 80% B in 3 minutes (A=waterwith 0.025% TFA, B=MeCN)) the diastereoisomers had the followingproperties:

Diastereoisomer 1. First peak. Retention time 1.855 min., LCMS calc. forC₂₄H₂₇F₂N₆O₃S (M+H)⁺: m/z=517.2. Found: 517.2.

Diastereoisomer 2. Second peak. Retention time 1.841 min., LCMS calc.for C₂₄H₂₇F₂N₆O₃S (M+H)⁺: m/z=517.2. Found: 517.2.

The diastereoisomers correspond to the (7R) and (7S) diastereoisomers ofthe title compound.

Example 545-Amino-N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluoro-3-methoxyphenyl)-1,3-thiazole-4-carboxamide

Step 1:3-({[5-[(tert-Butoxycarbonyl)amino]-2-(2,6-difluoro-3-methoxyphenyl)-1,3-thiazol-4-yl]carbonyl}amino)-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylAcetate

A mixture of3-amino-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (10.0 mg, 0.025 mmol),5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluoro-3-methoxyphenyl)-1,3-thiazole-4-carboxylicacid (9.6 mg, 0.025 mmol), HATU (23.5 mg, 0.062 mmol) in DMF (0.06 mL)and DIPEA (0.013 mL, 0.074 mmol) was stirred at room temperature for 3h. The mixture was diluted with MeOH and purified by preparative LC-MS(XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min.,eluting with a gradient of MeCN and water with 0.1% NH₄OH) to give thesub-title compound as a white powder (5.5 mg, 29%). LCMS calc. forC₃₇H₄₇F₂N₆O₈S (M+H)⁺: m/z=773.3. Found: 773.3.

Step 2:5-Amino-N-{4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2,6-difluoro-3-methoxyphenyl)-1,3-thiazole-4-carboxamide

A mixture of3-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluoro-3-methoxyphenyl)-1,3-thiazol-4-yl]carbonyl}amino)-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (5.5 mg, 0.007 mmol), MeOH (84 μL), THF (42 μL) and 1.0 M aq.NaOH (46 μL, 0.046 mmol) was stirred at room temperature for 20 min. Thesolvents were removed under reduced pressure to give a crudeintermediate, which was dissolved in DCM (0.07 mL), and TFA (0.072 mL,0.94 mmol) was then added. The reaction mixture was stirred at roomtemperature for 20 min. The solution was then concentrated under reducedpressure and the residue was diluted with MeOH, filtered and purified bypreparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm,60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH₄OH)to give both diastereoisomers as white powders. On analytical HPLC(Waters SunFire™ C18, 2.1×50 mm, 5 μm; flow rate 3 mL/min.; injectionvolume 2 μL; gradient from 2 to 80% B in 3 minutes (A=water with 0.025%TFA, B=MeCN)) the diastereoisomers had the following properties:

Diastereoisomer 1. First peak. Retention time 2.140 min., LCMS calc. forC₂₅H₂₉F₂N₆O₃S (M+H)⁺: m/z=531.2. Found: 531.2.

Diastereoisomer 2. Second peak. Retention time 2.267 min., LCMS calc.for C₂₅H₂₉F₂N₆O₃S (M+H)⁺: m/z=531.2. Found: 531.2.

Example 55N-{4-[(3S)-3-Aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxamide

Step 1: Methyl6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxylate

In a sealed tube to a mixture of methyl6-bromo-5-fluoropyridine-2-carboxylate (374 mg, 1.60 mmol) and(2,6-difluoro-3-methoxyphenyl)boronic acid (150 mg, 0.798 mmol) in THF(6.0 mL) and water (0.6 mL) was added potassium fluoride (153 mg, 2.64mmol). The reaction mixture was purged with N₂ for 5 min., thentris(dibenzylideneacetone)dipalladium (0) (180 mg, 0.20 mmol) andtri-tert-butylphosphine (81 mg, 0.40 mmol) were added subsequently. Thereaction mixture was then heated at 100° C. for 30 min. After filtrationand concentration of the solution under reduced pressure, the residuewas purified by silica gel column chromatography using CombiFlash® (0 to40% EtOAc in hexanes) to give the sub-title compound as a white powder(83.3 mg, 35%). LCMS calc. for C₁₄H₁₁F₃NO₃ (M+H)⁺: m/z=298.1. Found:298.2.

Step 2: 6-(2,6-Difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxylicacid

To a mixture of methyl6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxylate (82.9mg, 0.279 mmol) in THF (0.3 mL) and MeOH (0.3 mL) was added 1.0 M aq.NaOH (1.39 mL, 1.39 mmol). The reaction mixture was stirred at roomtemperature for 40 min., neutralized with HCl (12 M) to pH=7 andconcentrated under reduced pressure to remove the solvents. The residuewas dissolved in THF, dried, filtered and concentrated under reducedpressure to give the sub-title compound as a white powder (53.4 mg,68%). LCMS calc. for C₁₃H₉F₃NO₃ (M+H)⁺: m/z=284.1. Found: 284.2.

Step 3:4-{(3S)-3-[(tert-Butoxycarbonyl)amino]piperidin-1-yl}-3-({[6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylAcetate

A mixture of3-amino-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (13.6 mg, 0.035 mmol),6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxylic acid (9.0mg, 0.032 mmol), HATU (30.2 mg, 0.080 mmol) in DMF (0.07 mL) and DIPEA(0.017 mL, 0.095 mmol) was stirred at room temperature for 16 h. Themixture was diluted with MeOH and purified by preparative LC-MS(XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min.,eluting with a gradient of MeCN and water with 0.1% NH₄OH) to give thesub-title compound as a white powder (5.0 mg, 24%). LCMS calc. forC₃₃H₃₇F₃N₅O₆(M+H)⁺: m/z=656.3. Found: 656.3.

Step 4:N-{4-[(3S)-3-Aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxamide

A mixture of4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-3-({[6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (5.0 mg, 0.008 mmol), MeOH (90 μL), THF (45 μL) and 1.0 M aq.NaOH (50 μL, 0.050 mmol) was stirred at room temperature for 20 min. Thesolvents were removed under reduced pressure to give the crudeintermediate, which was dissolved in DCM (0.08 mL), followed by theaddition of TFA (0.078 mL, 1.0 mmol). The reaction mixture was stirredat room temperature for 20 min. After concentrating the solution underreduced pressure, the residue was diluted with MeOH, filtered andpurified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and waterwith 0.1% NH₄OH) to give both diastereoisomers of the title compound aswhite powders.

Diastereoisomer 1. First peak. Retention time 1.908 min., LCMS calc. forC₂₆H₂₇F₃N₅O₃(M+H)⁺: m/z=514.2; Found: 514.2.

Diastereoisomer 2. Second peak. Retention time 1.962 min., LCMS calc.for C₂₆H₂₇F₃N₅O₃(M+H)⁺: m/z=514.2; Found: 514.2.

The diastereoisomers correspond to the (7R) and (7S) diastereoisomers ofthe title compound.

Example 56N-{4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxamide

Step 1:4-{(3S,5R)-3-[(tert-Butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-3-({[6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylAcetate

A mixture of3-amino-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (14.1 mg, 0.035 mmol),6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxylic acid (9.0mg, 0.032 mmol), HATU (30.2 mg, 0.08 mmol) in DMF (0.07 mL) and DIPEA(0.017 mL, 0.095 mmol) was stirred at room temperature for 16 h. Themixture was diluted with MeOH and purified by preparative LC-MS(XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min.,eluting with a gradient of MeCN and water with 0.1% NH₄OH) to give thesub-title compound as a white powder (8.0 mg, 38%). LCMS calc. forC₃₄H₃₉F₃N₅O₆(M+H)⁺: m/z=670.3. Found: 670.3.

Step 2:N-{4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxamide

A mixture of4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-3-({[6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (8.0 mg, 0.012 mmol), MeOH (140 μL), THF (71 μL) and 1.0 M aq.NaOH (78 μL, 0.078 mmol) was stirred at room temperature for 20 min. Theorganic solvents were removed under vacuum and dried to give the crudeintermediate, which was dissolved in DCM (0.1 mL), followed by theaddition of TFA (0.12 mL, 1.6 mmol). The reaction mixture was stirred atroom temperature for 20 min. The solution was then concentrated underreduced pressure and the residue was diluted with MeOH, filtered andpurified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and waterwith 0.1% NH₄OH) to give both diastereoisomers of the title compound aswhite powders. On analytical HPLC (Waters SunFire™ C18, 2.1×50 mm, 5 μm;flow rate 3 mL/min.; injection volume 2 μL; gradient from 2 to 80% B in3 minutes (A=water with 0.025% TFA, B=MeCN)) the diastereoisomers hadthe following properties:

Diastereoisomer 1. First peak. Retention time 1.969 min., LCMS calc. forC₂₇H₂₉F₃N₅O₃(M+H)⁺: m/z=528.2. Found: 528.2.

Diastereoisomer 2. Second peak. Retention time 2.079 min., LCMS calc.for C₂₇H₂₉F₃N₅O₃(M+H)⁺: m/z=528.2. Found: 528.2.

The diastereoisomers correspond to the (7R) and (7S) diastereoisomers ofthe title compound.

Example 575-Amino-N-[4-(3-amino-3-methylpiperidin-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

Step 1: tert-Butyl[3-methyl-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate

A mixture of 4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (200mg, 1.01 mmol), tert-butyl (3-methylpiperidin-3-yl)carbamate (227 mg,1.06 mmol) and triethylamine (281 μL, 2.01 mmol) in isopropyl alcohol(1.2 mL) was stirred at 100° C. for 20 min. After cooling, the sub-titlecompound precipitated out and was collected by vacuum filtration,followed by washing with cold ether to give the sub-title compound aslight yellow powder. LCMS calc. for C₁₉H₂₉N₄O₄ (M+H)⁺: m/z=377.2. Found:377.2.

Step 2: tert-Butyl[1-(3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-3-methylpiperidin-3-yl]carbamate

A mixture of tert-butyl[3-methyl-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate(100.0 mg, 0.27 mmol), AcOH (1.44 mL) and iron powder (222 mg, 3.98mmol) was stirred at room temperature for 1 h. The reaction mixture wasdiluted with EtOAc, filtered through a short silica gel plug. Theresidue was rinsed with fresh EtOAc and filtered. The filtrate wasconcentrated under reduced pressure, diluted with EtOAc and neutralizedwith Na₂CO₃ solution. After vacuum filtration to remove insolubleimpurities, the aqueous layer was extracted with EtOAc three times. Thecombined organic layers were dried, filtered and concentrated underreduced pressure to give the sub-title compound as off-white powder (80mg, 90%). LCMS calc. for C₁₉H₃₁N₄O₂ (M+H)⁺: m/z=347.2. Found: 347.2.

Step 3: tert-Butyl{1-[3-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-3-methylpiperidin-3-yl}carbamate

A mixture of tert-butyl[1-(3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-3-methylpiperidin-3-yl]carbamate(8.0 mg, 0.023 mmol),5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylicacid (9.1 mg, 0.025 mmol), HATU (21.9 mg, 0.058 mmol) in DMF (0.05 mL)and DIPEA (0.012 mL, 0.069 mmol) was stirred at room temperature for 2h. The reaction mixture was diluted with MeOH and purified bypreparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm,60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH₄OH)to give the sub-title compound as a white powder (8.4 mg, 53%). LCMScalc. for C₃₄H₄₃F₂N₆O₅S (M+H)⁺: m/z=685.3. Found: 685.3.

Step 4:5-Amino-N-[4-(3-amino-3-methylpiperidin-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

A mixture of tert-butyl{1-[3-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-3-methylpiperidin-3-yl}carbamate(8.4 mg, 0.012 mmol), DCM (0.12 mL) and TFA (0.12 mL, 1.6 mmol) wasstirred at room temperature for 30 min. The solution was thenconcentrated under reduced pressure and the residue was diluted withMeOH, filtered and purified by preparative LC-MS (XBridge™ preparativeC18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient ofMeCN and water with 0.1% NH₄OH) to give the title compound as a whitepowder (3.5 mg, 59%). LCMS calc. for C₂₄H₂₇F₂N₆OS (M+H)⁺: m/z=485.2.Found: 485.2.

Example 58N-{4-[(3S)-3-Aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(methylthio)phenyl]-5-fluoropyridine-2-carboxamide

Step 1: 1, 3-Difluoro-5-(methylthio)benzene

Methyl iodide (2.91 g, 20.5 mmol) was added dropwise to a stirredmixture of 3,5-difluorobenzenethiol (2.00 g, 13.7 mmol) and potassiumcarbonate (5.67 g, 41.0 mmol) in dry MeCN (24 mL) at room temperature.The reaction mixture was stirred at 80° C. for 2 h. After cooling, themixture was filtered under vacuum, washed with MeCN and concentratedunder reduced pressure to give the sub-title compound, which was useddirectly in the next step without further purification (1.74 g, 80%).

Step 2:2-[2,6-Difluoro-4-(methylthio)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To a solution of 1,3-difluoro-5-(methylthio)benzene (0.800 g, 4.99 mmol)in dry THF (25 mL) under nitrogen at −78° C., n-BuLi in THF (1.6 M; 3.28mL, 5.24 mmol) was added slowly while keeping the internal temperaturebelow −65° C. The reaction mixture was stirred at −78° C. for 2 h.2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.07 g, 5.74 mmol)was then added. The reaction mixture was allowed to warm to roomtemperature for 2 h, and then quenched with aq. NaHCO₃ and extractedwith EtOAc. The organic extracts were washed with brine, dried, filteredand concentrated under reduced pressure to yield the crude sub-titlecompound (1.42 g, 99%) as a viscous liquid.

Step 3: Methyl6-[2,6-difluoro-4-(methylthio)phenyl]-5-fluoropyridine-2-carboxylate

In a sealed tube, a mixture of2-[2,6-difluoro-4-(methylthio)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1.00 g, 3.49 mmol), methyl 6-bromo-5-fluoropyridine-2-carboxylate (1.23g, 5.24 mmol) and DIPEA (1.83 mL, 10.5 mmol) in a mixed solvent of1,4-dioxane (15 mL) and water (0.51 mL) was stirred and flushed withnitrogen bubbles for 5 min. before bis(tri-tert-butylphosphine)palladium(360 mg, 0.70 mmol) was added. The reaction mixture was heated at 120°C. for 30 min. After cooling, the reaction mixture was filtered, and thefilter was washed with THF. The filtrate was concentrated and thenpurified by silica gel column chromatography using CombiFlash® (0 to 20%EtOAc in hexanes) to give the sub-title compound as powder (442 mg,40%). LCMS calc. for C₁₄H₁₁F₃NO₂S (M+H)⁺: m/z=314.1. Found: 314.2.

Step 4:6-[2,6-Difluoro-4-(methylthio)phenyl]-5-fluoropyridine-2-carboxylic acid

Methyl6-[2,6-difluoro-4-(methylthio)phenyl]-5-fluoropyridine-2-carboxylate(80.0 mg, 0.255 mmol) was dissolved in THF (0.3 mL) and MeOH (0.3 mL),then 1.0 M aq. NaOH (1.28 mL, 1.28 mmol) was added. The reaction mixturewas stirred at room temperature for 50 min., then neutralized with HCl(12 M) to pH=7 and concentrated under reduced pressure to remove all thesolvents. The residue was dissolved in THF, dried, filtered andconcentrated under vacuum to give the sub-title compound as a whitepowder (42 mg, 55%). LCMS calc. for C₁₃H₉F₃NO₂S (M+H)⁺: m/z=300.0.Found: 300.2.

Step 5:4-{(3S)-3-[(tert-Butoxycarbonyl)amino]piperidin-1-yl}-3-[({6-[2,6-difluoro-4-(methylthio)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylAcetate

A mixture of3-amino-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (12.0 mg, 0.031 mmol),6-[2,6-difluoro-4-(methylthio)phenyl]-5-fluoropyridine-2-carboxylic acid(11.0 mg, 0.037 mmol), HATU (29.2 mg, 0.077 mmol) in DMF (0.07 mL) andDIPEA (11.9 mg, 0.092 mmol) was stirred at room temperature for 16 h.The reaction mixture was filtered, concentrated and purified bypreparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm,60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH₄OH)to give the sub-title compound as a colorless gum (6.3 mg, 30%). LCMScalc. for C₃₃H₃₇F₃N₅O₅S (M+H)⁺: m/z=672.2. Found: 672.2.

Step 6:N-{4-[(3S)-3-Aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(methylthio)phenyl]-5-fluoropyridine-2-carboxamide

4-{(3S)-3-[(tert-Butoxycarbonyl)amino]piperidin-1-yl}-3-[({6-[2,6-difluoro-4-(methylthio)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (6.3 mg, 0.009 mmol) was dissolved in MeOH (0.1 mL) and THF(0.06 mL), then 1.0 M aq. NaOH (0.038 mL, 0.038 mmol) was added. Thereaction mixture was stirred at room temperature for 20 min. The organicsolvents and trace of water were removed under reduced pressure to givea crude intermediate. The residue was dissolved in DCM (0.1 mL) and thenTFA (0.095 mL, 1.2 mmol) was added. The reaction mixture was stirred atroom temperature for 20 min., then the solution was evaporated underreduced pressure. The residue was diluted with MeOH, filtered andpurified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and waterwith 0.1% NH₄OH) to give both diastereoisomers of the title compound aswhite powders. On analytical HPLC (Waters SunFire™ C18, 2.1×50 mm, 5 μm;flow rate 3 mL/min.; injection volume 2 μL; gradient from 2 to 80% B in3 minutes (A=water with 0.025% TFA, B=MeCN)), the diastereoisomers ofthe product had the following properties:

Diastereoisomer 1. First peak. Retention time 2.471 min., LCMS calc. forC₂₆H₂₇F₃N₅O₂S (M+H)⁺: m/z=530.2. Found: 530.2.

Diastereoisomer 2. Second peak. Retention time 2.551 min., LCMS calc.for C₂₆H₂₇F₃N₅O₂S (M+H)⁺: m/z=530.2. Found: 530.2.

The diastereoisomers correspond to the (7R) and (7S) diastereoisomers ofthe title compound.

Example 59N-{4-[(3S)-3-Aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(methylsulfinyl)phenyl]-5-fluoropyridine-2-carboxamide

Step 1: Methyl6-[2,6-difluoro-4-(methylsulfinyl)phenyl]-5-fluoropyridine-2-carboxylate

To a solution of methyl6-[2,6-difluoro-4-(methylthio)phenyl]-5-fluoropyridine-2-carboxylate(150 mg, 0.479 mmol) in DCM (3.0 mL) was added potassiumperoxymonosulfate (147 mg, 0.958 mmol) at room temperature. The reactionmixture was stirred at room temperature for 2 h. The solution waspartitioned between EtOAc and water. The organic layer was dried,filtered. The filtrate was concentrated and then purified by silica gelcolumn chromatography using CombiFlash® (0 to 100% EtOAc in hexanes) togive the sub-title compound as a white powder (37 mg, 23%). LCMS calc.for C₁₄H₁₁F₃NO₃S (M+H)⁺: m/z=330.0. Found: 330.2.

Step 2:6-[2,6-Difluoro-4-(methylsulfinyl)phenyl]-5-fluoropyridine-2-carboxylicacid

Methyl6-[2,6-difluoro-4-(methylsulfinyl)phenyl]-5-fluoropyridine-2-carboxylate(37.0 mg, 0.112 mmol) was dissolved in THF (0.12 mL) and MeOH (0.12 mL),and 1.0 M aq. NaOH (0.56 mL, 0.56 mmol) was then added. The reactionmixture was stirred at room temperature for 50 min. The mixture was thenneutralized with HCl (12 M) to pH=7 and concentrated under reducedpressure to remove all the solvents. The residue was dissolved in THF,dried, filtered and concentrated under reduced pressure to give thesub-title compound as a white powder. LCMS calc. for C₁₃H₉F₃NO₃S (M+H)⁺:m/z=316.0. Found: 316.2.

Step 3:4-{(3S)-3-[(tert-Butoxycarbonyl)amino]piperidin-1-yl}-3-[({6-[2,6-difluoro-4-(methylsulfinyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylAcetate

A mixture of3-amino-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (12.0 mg, 0.031 mmol),6-[2,6-difluoro-4-(methylsulfinyl)phenyl]-5-fluoropyridine-2-carboxylicacid (11.6 mg, 0.037 mmol), HATU (29.2 mg, 0.077 mmol) in DMF (0.07 mL)and DIPEA (11.9 mg, 0.092 mmol) was stirred at room temperature for 16h. The reaction mixture was filtered, concentrated under reducedpressure and purified by preparative LC-MS (XBridge™ preparative C18 5μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCNand water with 0.1% NH₄OH) to give the sub-title compound as a colorlessgum (3.0 mg, 14%). LCMS calc. for C₃₃H₃₇F₃N₅O₆S (M+H)⁺: m/z=688.2.Found: 688.2.

Step 4:N-{4-[(3S)-3-Aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(methylsulfinyl)phenyl]-5-fluoropyridine-2-carboxamide

4-{(3S)-3-[(tert-Butoxycarbonyl)amino]piperidin-1-yl}-3-[({6-[2,6-difluoro-4-(methylsulfinyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (3.0 mg, 0.0044 mmol) was dissolved in MeOH (0.01 mL) and THF(0.05 mL), and 1.0 M aq. NaOH (0.017 mL, 0.017 mmol) was then added. Thereaction mixture was stirred at room temperature for 60 min. The organicsolvents and trace of water were removed under reduced pressure to givea crude intermediate. The residue was dissolved in DCM (0.04 mL), thenTFA (0.044 mL, 0.58 mmol) was added. The reaction mixture was stirred atroom temperature for 16 h. The solution was then concentrated againunder reduced pressure. The residue was diluted with MeOH, filtered andpurified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and waterwith 0.1% NH₄OH) to give two mixtures of diastereoisomers of the titlecompound as white powders. On analytical HPLC (Waters SunFire™ C18,2.1×50 mm, 5 μm; flow rate 3 mL/min.; injection volume 2 μL; gradientfrom 2 to 80% B in 3 minutes (A=water with 0.025% TFA, B=MeCN)) thediastereoisomers had the following properties:

Diastereoisomer 1. First peak. Retention time 1.371 min., LCMS calc. forC₂₆H₂₇F₃N₅O₃S (M+H)⁺: m/z=546.2. Found: 546.2.

Diastereoisomer 2. Second peak. Retention time 1.440 min., LCMS calc.for C₂₆H₂₇F₃N₅O₃S (M+H)⁺: m/z=546.2. Found: 546.2.

The diastereoisomers are tentatively assigned as the separated (7R) and(7S) diastereoisomers of the title compound, each being a mixture ofdiastereoisomers having (R) and (S) configuration of the sulfoxidesulfur atom.

Example 60N-{4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(methylsulfinyl)phenyl]-5-fluoropyridine-2-carboxamide

Step 1:4-{(3S,5R)-3-[(tert-Butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-3-[({6-[2,6-difluoro-4-(methylsulfinyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylAcetate

A mixture of3-amino-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (10.0 mg, 0.025 mmol),6-[2,6-difluoro-4-(methylsulfinyl)phenyl]-5-fluoropyridine-2-carboxylicacid (9.4 mg, 0.03 mmol), HATU (23.5 mg, 0.062 mmol) in DMF (0.06 mL)and DIPEA (9.6 mg, 0.074 mmol) was stirred at room temperature for 16 h.The mixture was filtered, concentrated and purified by preparative LC-MS(XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min.,eluting with a gradient of MeCN and water with 0.1% NH₄OH) to give thesub-title compound as a colorless gum (3.0 mg, 17%). LCMS calc. forC₃₄H₃₉F₃N₅O₆S (M+H)⁺: m/z=702.3. Found: 702.2.

Step 2:N-{4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(methylsulfinyl)phenyl]-5-fluoropyridine-2-carboxamide

4-{(3S,5R)-3-[(tert-Butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-3-[({6-[2,6-difluoro-4-(methylsulfinyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (3.0 mg, 0.0043 mmol) was dissolved in MeOH (0.02 mL) and THF(0.08 mL), followed by the addition of 1.0 M aq. NaOH (0.017 mL, 0.017mmol). The reaction mixture was stirred at room temperature for 20 min.The organic solvents and trace of water were removed under vacuum togive the crude intermediate, which was dissolved in DCM (0.044 mL),followed by the addition of TFA (0.044 mL, 0.56 mmol). The reactionmixture was stirred at room temperature for 20 min. After concentration,the residue was diluted with MeOH, filtered and purified by preparativeLC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min.,eluting with a gradient of MeCN and water with 0.1% NH₄OH) to give twomixtures of diastereoisomers of the title compound as white powders. Onanalytical HPLC (Waters SunFire™ C18, 2.1×50 mm, 5 μm; flow rate 3mL/min.; injection volume 2 μL; gradient from 2 to 80% B in 3 minutes(A=water with 0.025% TFA, B=MeCN)) the diastereoisomers had thefollowing properties:

Diastereoisomer 1. First peak. Retention time 1.858 min., LCMS calc. forC₂₇H₂₉F₃N₅O₃S (M+H)⁺: m/z=560.2. Found: 560.2.

Diastereoisomer 2. Second peak. Retention time 1.975 min., LCMS calc.for C₂₇H₂₉F₃N₅O₃S (M+H)⁺: m/z=560.2. Found: 560.2.

The diastereoisomers are tentatively assigned as the separated (7R) and(7S) diastereoisomers of the title compound, each being a mixture ofdiastereoisomers having (R) and (S) configuration of the sulfoxidesulfur atom.

Example 61N-{4-[(3S)-3-Aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(methylsulfonyl)phenyl]-5-fluoropyridine-2-carboxamide

Step 1: Methyl6-[2,6-difluoro-4-(methylsulfonyl)phenyl]-5-fluoropyridine-2-carboxylate

To a solution of methyl6-[2,6-difluoro-4-(methylthio)phenyl]-5-fluoropyridine-2-carboxylate(81.0 mg, 0.258 mmol) in DCM (1.2 mL) at 0° C. was added mCPBA (185 mg,0.827 mmol). The reaction mixture was stirred at 0° C. for 2 h, followedby the addition of Na₂S₂O₃ solution and then 1 M NaOH. The reactionmixture was stirred for 20 min. at room temperature, then extracted withDCM three times. The combined organic layers were dried over Na₂SO₄,filtered and concentrated under reduced pressure to give the sub-titlecompound (78 mg, 87%). LCMS calc. for C₁₄H₁₁F₃NO₄S (M+H)⁺: m/z=346.0;Found: 346.2.

Step 2:6-[2,6-Difluoro-4-(methylsulfonyl)phenyl]-5-fluoropyridine-2-carboxylicacid

Methyl6-[2,6-difluoro-4-(methylsulfonyl)phenyl]-5-fluoropyridine-2-carboxylate(78.0 mg, 0.226 mmol) was dissolved in THF (0.2 mL) and MeOH (0.2 mL),and 1.0 M aq. NaOH (0.90 mL, 0.90 mmol) was then added. The reactionmixture was stirred at room temperature for 40 min. The solution wasthen neutralized with HCl (12 M) to pH=7 and concentrated under reducedpressure to remove all the solvents. The residue was dissolved in THFand MeOH, dried, filtered and concentrated under reduced pressure togive the sub-title compound as a white powder. LCMS calc. forC₁₃H₉F₃NO₄S (M+H)⁺: m/z=332.0. Found: 332.2.

Step 3:4-{(3S)-3-[(tert-Butoxycarbonyl)amino]piperidin-1-yl}-3-[({6-[2,6-difluoro-4-(methylsulfonyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylAcetate

A mixture of3-amino-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (15.0 mg, 0.0384 mmol),6-[2,6-difluoro-4-(methylsulfonyl)phenyl]-5-fluoropyridine-2-carboxylicacid (15.3 mg, 0.0461 mmol), HATU (36.5 mg, 0.0960 mmol) in DMF (0.09mL) and DIPEA (14.9 mg, 0.115 mmol) was stirred at room temperature for16 h. The mixture was filtered, concentrated under reduced pressure andpurified by preparative LC-MS (method; XBridge™ preparative C18 5 μmOBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN andwater with 0.1% NH₄OH) to give the sub-title compound as a colorless gum(11.0 mg, 41%). LCMS calc. for C₃₃H₃₇F₃N₅O₇S (M+H)⁺: m/z=704.2. Found:704.2.

Step 4:N-{4-[(3S)-3-Aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(methylsulfonyl)phenyl]-5-fluoropyridine-2-carboxamide

4-{(3S)-3-[(tert-Butoxycarbonyl)amino]piperidin-1-yl}-3-[({6-[2,6-difluoro-4-(methylsulfonyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (11.0 mg, 0.0156 mmol) was dissolved in MeOH (0.04 mL) and THF(0.20 mL), then 1.0 M aq. NaOH (0.062 mL, 0.062 mmol) was added. Thereaction mixture was stirred at room temperature for 30 min. The organicsolvents and trace of water were removed under vacuum to give a crudeintermediate. The intermediate was dissolved in DCM (0.16 mL) and TFA(0.16 mL, 2.1 mmol) was then added. The reaction mixture was stirred atroom temperature for 30 min. The solution was concentrated under reducedpressure and the residue was diluted with MeOH, filtered and purified bypreparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm,60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH₄OH)to give both diastereoisomers of the title compound as white powders. Onanalytical HPLC (Waters SunFire™ C18, 2.1×50 mm, 5 μm; flow rate 3mL/min.; injection volume 2 μL; gradient from 2 to 80% B in 3 minutes(A=water with 0.025% TFA, B=MeCN)), the diastereoisomers had thefollowing properties:

Diastereoisomer 1. First peak. Retention time 1.542 min., LCMS calc. forC₂₆H₂₇F₃N₅O₄S (M+H)⁺: m/z=562.2. Found: 562.2.

Diastereoisomer 2. Second peak. Retention time 1.611 min., LCMS calc.for C₂₆H₂₇F₃N₅O₄S (M+H)⁺: m/z=562.2. Found: 562.2.

The diastereoisomers correspond to the (7R) and (7S) diastereoisomers ofthe title compound.

Example 623-Amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)pyrazine-2-carboxamide

Step 1. Methyl 3-amino-6-(2,6-difluorophenyl)pyrazine-2-carboxylate

A solution of (2,6-difluorophenyl)boronic acid (270 mg, 1.7 mmol),methyl 3-amino-6-bromopyrazine-2-carboxylate (from Ark Pharm, 250 mg,1.1 mmol), bis(tri-tert-butylphosphine) palladium (82 mg, 0.16 mmol),and DIPEA (370 μL, 2.1 mmol) in 1,4-dioxane (4 mL) and water (320 μL) ina vial was deoxygenated and purged with nitrogen several times. The vialwas sealed and the reaction mixture was heated at 100° C. in the sealedvial for 14 h. The crude reaction mixture was filtered through a pad ofdiatomaceous earth and the inorganics were washed thoroughly with EtOAc.The filtrate was concentrated under reduced pressure and the residue waspurified by flash chromatography (40 g silica gel column, eluting with0-50% EtOAc in hexanes) to afford the sub-title compound (258 mg, 91%yield). LC/MS (ESI) calc. for C₁₂H₁₀F₂N₃O₂ (M+H)⁺: m/z=266.1; found:266.0.

Step 2. 3-Amino-6-(2,6-difluorophenyl)pyrazine-2-carboxylic acid

A solution of methyl3-amino-6-(2,6-difluorophenyl)pyrazine-2-carboxylate (258 mg, 0.973mmol) and lithium hydroxide monohydrate (200 mg, 4.8 mmol) in THF (4.0mL) and water (2.0 mL) was heated at 60° C. in a sealed vial for 2 h.The reaction mixture was allowed to cool to ambient temperature andneutralized by the addition of 1.0 M hydrogen chloride in water (4.8 mL,4.8 mmol) to form a precipitate. The precipitate was collected byfiltration, washed with EtOAc (5 mL), and dried under vacuum to affordthe sub-title compound (170 mg). The filtrate was diluted with EtOAc (15mL) and the layers were separated. The organic layer was washed with H₂O(3 mL) and the combined aqueous phases were extracted with EtOAc (3 mL).The combined organic layers were washed with brine (3 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to provideadditional sub-title compound. The crude product was used in thesubsequent reaction without further purification (70 mg). LC/MS (ESI)calc. for C₁₁H₈F₂N₃O₂ (M+H)⁺: m/z=252.1; found: 251.9.

Step 3.3-({[3-Amino-6-(2,6-difluorophenyl)pyrazin-2-yl]carbonyl}amino)-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylAcetate

To a pre-stirred solution of3-amino-6-(2,6-difluorophenyl)pyrazine-2-carboxylic acid (18 mg, 0.070mmol), HATU (32 mg, 0.084 mmol), and DIPEA (36 μL, 0.21 mmol) in1,2-dichloroethane (0.3 mL) was added a solution of3-amino-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (38 mg, 0.097 mmol) in 1,2-dichloroethane (0.5 mL). Theresulting solution was stirred at ambient temperature for 3 h. The crudereaction mixture was concentrated under reduced pressure and the residuewas purified by flash chromatography (20 g silica gel column, elutingwith 0-10% MeOH in DCM) to afford the sub-title compound (18 mg, 41%).LC/MS (ESI) calc. for C₃₁H₃₆F₂N₇O₅(M+H)⁺: m/z=624.3; found: 624.1.

Step 4.3-Amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)pyrazine-2-carboxamide

A solution of3-({[3-amino-6-(2,6-difluorophenyl)pyrazin-2-yl]carbonyl}amino)-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (18 mg, 0.029 mmol) and lithium hydroxide [1.0]-water (11.1 mg,0.264 mmol) in MeOH (300 μL) and water (300 μL) was stirred at ambienttemperature for 1.5 h. The reaction mixture was diluted with EtOAc (20mL) and neutralized with 1.0 M hydrogen chloride in water (260 μL, 0.26mmol). The layers were separated and the organic layer was washed withH₂O (3 mL) and the combined aqueous phases were extracted with EtOAc (3mL×3). The combined organic layers were washed with brine (3 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to affordan intermediate (13 mg, 87%). The crude intermediate was dissolved in1,2-dichloroethane (300 μL) and TFA (300 μL, 3.89 mmol), and theresulting solution was stirred at ambient temperature for 1.5 h. Thecrude reaction mixture was concentrated under reduced pressure and theresidue was purified by preparative HPLC (XBridge™ preparative C18 5 μmOBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN andwater with 0.05% TFA) to afford the tris(trifluoroacetate) salt of thetitle compound as two diastereoisomers. On analytical HPLC (WatersSunFire™ C18, 2.1×50 mm, 5 μm; flow rate 3 mL/min.; injection volume 2μL; gradient from 2 to 80% B in 3 minutes (A=water with 0.025% TFA,B=MeCN)), the diastereoisomers had the following properties:

Diastereoisomer 1. First peak. Retention time 0.88 min., LC/MS (ESI)calc. for C₂₄H₂₆F₂N₇O₂(M+H)⁺: m/z=482.2; found: 482.0.

Diastereoisomer 2. Second peak. Retention time 0.94 min., LC/MS (ESI)calc. for C₂₄H₂₆F₂N₇O₂(M+H)⁺: m/z=482.2; found: 482.0.

The diastereoisomers correspond to the (7R) and (7S) diastereoisomers ofthe title compound.

Example 63N-{4-[(3R,5S)-3-Amino-4-hydroxy-4,5-dimethylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

Step 1.Benzyl-(3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidine-1-carboxylate

To a solution oftert-butyl-((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(3.2 g, 9.4 mmol) (40% purity) in DCM (25 mL),N-(benzyloxycarbonyloxy)succinimide (2.6 g, 10 mmol) was added, followedby triethylamine (1.4 mL, 10 mmol). The mixture was stirred for 16 h atroom temperature. The reaction mixture was then diluted with EtOAc,washed with water and brine and dried over Na₂SO₄. The solvent wasevaporated under reduced pressure and the resulting crude product waspurified by silica gel chromatography eluting with 25% EtOAc in hexanesto give the sub-title compound as a white solid (1.71 g, 38%). LCMScalc. for C₂₅H₄₂N₂O₅SiNa (M+Na)⁺ m/z=501.3; found 501.0.

Step 2.Benzyl-(3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxy-5-methylpiperidine-1-carboxylate

Benzyl-(3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-5-methyl-4-(1,1,2,2-tetramethylpropoxy)piperidine-1-carboxylate(1.88 g, 4.06 mmol) was dissolved in THF (20 mL) and a 1.0 M solution oftetra-n-butylammonium fluoride in THF (4.7 mL, 4.7 mmol) was added. Thereaction mixture was stirred for 30 min. at room temperature and thendiluted with EtOAc. The mixture was washed 2 times with brine, thendried and concentrated under reduced pressure. The crude product waspurified by silica gel chromatography eluting with 25-75% EtOAc inhexanes to give the sub-title compound as a white solid (1.48 g, 82%).LCMS calc. for C₁₉H₂₈N₂NaO₅ (M+Na)⁺ m/z=387.2; found 387.0.

Step 3.Benzyl-3-[(tert-butoxycarbonyl)amino]-5-methyl-4-oxopiperidine-1-carboxylate

Pyridine (0.8 mL, 10 mmol) and Dess-Martin periodinane (1.8 g, 4.4 mmol)were added to a stirred solution ofbenzyl-3-[(tert-butoxycarbonyl)amino]-4-hydroxy-5-methylpiperidine-1-carboxylate(1.22 g, 3.35 mmol) in DCM (20 mL) at 0° C. The reaction mixture wasstirred at room temperature for 16 h. A solution containing a mixture ofNaHCO₃ and Na₂S₂O₃ was added and the resulting mixture was stirred for30 min. The mixture was then extracted with DCM. The combined organiclayers were dried over Na₂SO₄ and concentrated under reduced pressure.The resulting residue was purified by silica gel chromatography elutingwith 40% EtOAc in hexanes to give the sub-title compound as a colorlessoil (1.15 g, 95%). LCMS calc. for C₁₉H₂₆N₂NaO₅ (M+Na)+m/z=385.2; found385.0.

Step 4.Benzyl-(3R,5S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxy-4,5-dimethylpiperidine-1-carboxylate

To a solution ofbenzyl-(3R,5S)-3-[(tert-butoxycarbonyl)amino]-5-methyl-4-oxopiperidine-1-carboxylate(1.61 g, 4.44 mmol) in THF (30 mL) at −78° C. a solution ofmethylmagnesium bromide in ether (3.0 M, 4.4 mL, 13 mmol) was added. Thereaction was then quenched by adding aq. NH₄Cl, and the resultingmixture was extracted with EtOAc. The combined organic extracts weredried and concentrated under reduced pressure. The residue was purifiedby silica gel chromatography eluting with 20-80% EtOAc in hexanes togive a mixture of the two diastereoisomers of the sub-title compound asa colorless oil (0.95 g, 56%). LCMS calc. for C₂₀H₃₀N₂NaO₅ (M+Na)⁺m/z=401.2; found 401.0. 40% of unreacted starting material was alsoisolated.

Step 5.tert-Butyl-[(3R,5S)-4-hydroxy-4,5-dimethylpiperidin-3-yl]carbamate

Benzyl-(3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxy-4,5-dimethylpiperidine-1-carboxylate(414 mg, 1.09 mmol) in a vial was dissolved in MeOH (10 mL) and 10%palladium on carbon (100 mg) was added. The vial was closed with septumand connected to a balloon filled with hydrogen. The reaction mixturewas stirred at room temperature overnight. The solution was filtered toremove the palladium on carbon and solvent was evaporated under reducedpressure to give the sub-title compound as a colorless oil (245 mg,92%), which was used in the next step without further purification. LCMScalc. for C₁₂H₂₅N₂O₃ (M+H)⁺ m/z=245.2; found 245.1.

Step 6. tert-Butyl[(3R,5S)-4-hydroxy-4,5-dimethyl-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate

A mixture of 4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (210mg, 1.0 mmol), tert-butyl[(3R,5S)-4-hydroxy-4,5-dimethylpiperidin-3-yl]carbamate (255 mg, 1.04mmol) and triethylamine (296 μL, 2.12 mmol) in isopropyl alcohol (1 mL)was stirred at 80° C. for 2 h. The solvent was evaporated under reducedpressure and the resulting residue was purified by chromatography onsilica gel eluting with 25% EtOAc in hexanes to give the sub-titlecompound as a yellow oil (318 mg, 74%). LCMS calc. for C₂₀H₃₁N₄O₅ (M+H)⁺m/z=407.2; found 407.2.

Step 7. tert-Butyl[(3R,5S)-4-hydroxy-4,5-dimethyl-1-(3-nitro-1-oxido-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate

mCPBA (260 mg, 1.5 mmol) was added to a mixture of tert-butyl[(3R,5S)-4-hydroxy-4,5-dimethyl-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate(312 mg, 0.768 mmol) in DCM (3.2 mL). After 2 h, LCMS showed only 30%conversion of starting material. mCPBA was added several more times (toa total amount of about 10 eq.) until LCMS showed complete consumptionof starting material (after approximately 7 h). A saturated solution ofNaHCO₃ was then added to the mixture and the resulting mixture wasextracted with DCM. The combined organic extracts were dried and thenconcentrated to dryness under reduced pressure. The crude sub-titlecompound was used in the next step without further purification. LCMScalc. for C₂₀H₃₁N₄O₆ (M+H)⁺ m/z=423.2; found 423.2.

Step 8.4-{(3R,5S)-3-[(tert-Butoxycarbonyl)amino]-4-hydroxy-4,5-dimethylpiperidin-1-yl}-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylAcetate

A mixture of tert-butyl[(3R,5S)-4-hydroxy-4,5-dimethyl-1-(3-nitro-1-oxido-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate(390 mg, 0.92 mmol) and Ac₂O (2 mL) was stirred at 90° C. for 1 h. Thereaction mixture was cooled to room temperature and then concentratedunder reduced pressure. The mixture was neutralized with aq. NaHCO₃ andthen extracted with EtOAc. The combined organic extracts were dried andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel chromatography eluting with 20-80% EtOAc in hexanes togive the desired product as a yellow oil (196 mg, 55% in 2 steps). LCMScalc. for C₂₂H₃₃N₄O₇ (M+H)⁺ m/z=465.2; found 465.1.

Step 9.3-Amino-4-{(3R,5S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxy-4,5-dimethylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylAcetate

4-{(3R,5S)-3-[(tert-Butoxycarbonyl)amino]-4-hydroxy-4,5-dimethylpiperidin-1-yl}-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (198 mg, 0.426 mmol) was dissolved in acetic acid (2.8 mL), andiron powder (0.36 g, 6.4 mmol) was added to the solution. Reaction wasstirred at room temperature for 2 h. The mixture was diluted with 30 mLof EtOAc, filtered through diatomaceous earth. The filtrate wasconcentrated under reduced pressure and the resulting residue wasdissolved in EtOAc, and neutralized with NaHCO₃. The layers wereseparated, and the aqueous layer was extracted with further EtOAc. Thecombined organic layers were dried and concentrated under reducedpressure to give the sub-title compound as a white solid (176 mg, 95%),which was used in the next step without further purification. LCMS calc.for C₂₂H₃₅N₄O₅ (M+H)⁺ m/z=435.3; found 435.1.

Step 10.4-{(3R,5S)-3-[(tert-Butoxycarbonyl)amino]-4-hydroxy-4,5-dimethylpiperidin-1-yl}-3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylAcetate

3-Amino-4-{(3R,5S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxy-4,5-dimethylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (153 mg, 0.352 mmol),6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (107 mg, 0.422mmol), HATU (330 mg, 0.88 mmol), and DIPEA (180 μL, 1.0 mmol) weredissolved in DMF (4.9 mL) and the resulting mixture was stirred at roomtemperature for 2 h. The reaction mixture was diluted with MeCN andpurified by RP-HPLC (Waters SunFire™ C18 column, 19 mm×100 mm, 5 μmparticle size, eluting with a gradient of MeCN/water containing 0.1%TFA, at flow rate of 30 mL/min.) to give the sub-title compound as awhite solid (118 mg, 50%). LCMS calc. for C₃₄H₃₉F₃N₅O₆(M+H)⁺ m/z=670.3;found 670.3.

Step 11.N-{4-[(3R,5S)-3-Amino-4-hydroxy-4,5-dimethylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

4-{(3R,5S)-3-[(tert-Butoxycarbonyl)amino]-4-hydroxy-4,5-dimethylpiperidin-1-yl}-3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (118 mg, 0.176 mmol) was dissolved in a mixture of MeOH (1 mL)and THF (1 mL) and 0.5 M solution of aq. NaOH (1 mL, 0.5 mmol) wasadded. The reaction was stirred for 1 h, and then concentrated to dryunder reduced pressure. To the residue was added 4.0 M solution ofhydrogen chloride in dioxane (3 mL, 10 mmol). The reaction mixture wasstirred for 1 h, and then evaporated to dryness. The resulting residuewas dissolved in MeCN and purified by RP-HPLC (water SunFire™ C18column, 19 mm×100 mm, 5 μm particle size, eluting with a gradient ofMeCN/water containing 0.1% TFA, at flow rate of 30 mL/min.) to give fourdifferent diastereoisomers of the bis(trifluoroacetate) of the titlecompound as white solids.

Diastereoisomer 1. First peak. Retention time 1.402 min. LCMS calc. forC₂₇H₂₉F₃N₅O₃(M+H)⁺ m/z=528.2; found: 528.2. ¹H NMR (500 MHz, DMSO-d₆) δ10.49 (s, 1H), 8.74 (s, 1H), 8.36 (dd, J=8.7, 4.0 Hz, 1H), 8.21 (t,J=8.8 Hz, 1H), 8.14 (s, 3H), 7.71-7.61 (m, 1H), 7.31 (t, J=8.3 Hz, 2H),5.16 (t, J=6.9 Hz, 1H), 3.55 (d, J=9.7 Hz, 1H), 3.33 (t, J=12.1 Hz, 1H),3.25 (d, J=11.3 Hz, 1H), 3.14 (dq, J=12.0, 4.2, and 3.4 Hz, 1H), 3.05(s, 1H), 2.97-2.80 (m, 2H), 1.97-1.83 (m, 1H), 1.73 (dt, J=11.4 and 6.6Hz, 1H), 0.98 (s, 3H), 0.63 (d, J=6.8 Hz, 3H) ppm.

Diastereoisomer 2. Second peak. Retention time 1.445 min. LCMS calc. forC₂₇H₂₉F₃N₅O₃(M+H)⁺ m/z=528.2; found: 528.2.

Diastereoisomer 3. Third peak. Retention time 1.587 min. LCMS calc. forC₂₇H₂₉F₃N₅O₃(M+H)⁺ m/z=528.2; found: 528.2. ¹H NMR (500 MHz, DMSO-d₆) δ10.48 (s, 1H), 8.82 (s, 1H), 8.37 (dd, J=8.6 and 3.9 Hz, 1H), 8.22 (t,J=8.8 Hz, 1H), 8.03 (s, 2H), 7.67 (p, J=8.1 Hz, 1H), 7.31 (t, J=8.2 Hz,2H), 5.13-5.05 (m, 1H), 3.41 (d, J=10.7 Hz, 1H), 3.24 (t, J=12.1 Hz,1H), 3.13-3.02 (m, 1H), 3.03-2.81 (m, 2H), 2.46-2.38 (m, 1H), 1.91 (dq,J=13.2, 7.1 Hz, 1H), 1.80-1.66 (m, 1H), 0.97 (s, 3H), 0.67 (d, J=6.7 Hz,3H).

Diastereoisomer 4. Fourth peak. Retention time 1.658 min. LCMS calc. forC₂₇H₂₉F₃N₅O₃(M+H)⁺ m/z=528.2; found: 528.2.

The diastereoisomers correspond to the (3R,4R,5R,7R), (3R,4S,5R,7R),(3R,4R,5R,7S), and ((3R,4S,5R,7S) diastereoisomers of the titlecompound.

Example 64N-{4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridine-2-carboxamide

Step 1. (3,5-Difluorophenyl)methanol

To a solution of 3,5-difluorobenzaldehyde (2.00 g, 14.1 mmol) in MeOH(20 mL) at 0-5° C. was added NaBH₄ (1.06 g, 28.1 mmol) portionwise. Themixture was stirred at 0-5° C. for 1 h, quenched with brine, and thenextracted with EtOAc (2×). The combined organic phases were washed withwater and brine, then dried over Na₂SO₄ and concentrated under reducedpressure to give sub-title compound as a colorless oil. %). ¹H NMR (300MHz, CDCl₃) δ 6.88 (m, 2H), 6.70 (m, 1H), 4.69 (s, 2H), 1.88 (br s, 1H)ppm.

Step 2. 1, 3-Difluoro-5-(methoxymethyl)benzene

To a solution of (3,5-difluorophenyl)methanol (1.98 g, 13.7 mmol) in THF(20 mL) at 0° C. was added sodium hydride (1.0 g, 25 mmol) in portions.The mixture was stirred at 0-5° C. for 1 h, and then methyl iodide (4.3mL, 69 mmol) was added. The reaction mixture was stirred at roomtemperature for 2 h. The mixture was quenched with water and extractedwith EtOAc. The combined organic extracts were concentrated and theresulting residue was columned on 40 g silica gel, eluting with 0-40%EtOAc in hexanes, to give a colorless oil (2.1 g, 97%). ¹H NMR (300 MHz,CDCl₃) δ 6.86 (m, 2H), 6.71 (m, 1H), 4.43 (s, 2H), 3.38 (s, 3H) ppm.

Step 3.2-[2,6-Difluoro-4-(methoxymethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To a solution of 1,3-difluoro-5-(methoxymethyl)benzene (0.970 g, 6.13mmol) in THF (24 mL) at −78° C., a solution of n-BuLi in hexanes (1.6 M,9.58 mL, 15.3 mmol) was slowly added through a dripping funnel. Whenaddition was done, the mixture was kept at −78° C. for 1 h.2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.75 mL, 18.4mmol) was then added in one portion. The reaction mixture was allowed towarm to room temperature and stirred for 1 h. The mixture was quenchedwith aq. NaHCO₃ and extracted with EtOAc. The combined organic extractswere washed with brine, dried over Na₂SO₄, and concentrated underreduced pressure to give sub-title compound as a colorless oil. ¹H NMR(300 MHz, CDCl₃) δ 6.82 (m, 2H), 4.43 (s, 2H), 3.38 (s, 3H), 1.37 (s,12H) ppm.

Step 4.6-[2,6-Difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridine-2-carboxylicAcid

A mixture of2-[2,6-difluoro-4-(methoxymethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(0.364 g, 1.28 mmol), methyl 6-bromo-5-fluoropyridine-2-carboxylate(0.300 g, 1.28 mmol) and DIPEA (0.67 mL, 3.8 mmol) in 1,4-dioxane (6 mL)and water (0.30 mL) was purged with nitrogen.Bis(tri-tert-butylphosphine)palladium (65.5 mg, 0.128 mmol) was added tothe mixture. The resulting reaction mixture was then heated at 120° C.for 40 min. The mixture was filtered through a pad of diatomaceous earthand the filtrate was concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography (eluting with0-50% EtOAc in hexanes) to give methyl6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridine-2-carboxylateas a white powder.

The methyl6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridine-2-carboxylatewas treated with THF (2 mL), MeOH (2 mL) and 1.0 M aq. NaOH (2 mL, 2mmol) at room temperature for 1 h. The volatile solvents were removedunder reduced pressure. The residue was neutralized to pH around 5-6with 1N HCl. The solids that precipitated were collected by filtration,rinsed with water, and dried to give the sub-title compound as a whitesolid (374 mg, 98.2%). LCMS calc. for C₁₄H₁₁F₃NO₃ (M+H)⁺ m/z=298.1;found: 298.0.

Step 5.N-{4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridine-2-carboxamide

A mixture of3-amino-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (256 mg, 0.633 mmol),6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridine-2-carboxylicacid (188 mg, 0.633 mmol), HATU (481 mg, 1.26 mmol) in DMF (1 mL) andDIPEA (0.330 mL, 1.90 mmol) was stirred at room temperature for 2 h. Thereaction mixture was quenched with water and then extracted with EtOAc(2 times). The combined organic extracts were washed with brine, driedover Na₂SO₄, and concentrated under reduced pressure. The resultingresidue was purified by column chromatography on silica gel usingCombiFlash® apparatus eluting with EtOAc/hexanes (50-100%) to yield4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-3-[({6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate as an intermediate.

To the amide intermediate, THF (6 mL), MeOH (6 mL) and 1.0 M aq. NaOH(6.32 mL, 6.32 mmol) were added. The mixture was stirred at roomtemperature for 20 min. The volatile solvents were removed under reducedpressure. The resulting residue was extracted with EtOAc (2×). Thecombined organic phases were washed with brine, dried over Na₂SO₄, andthen concentrated to dry to give tert-butyl((3S,5R)-1-{3-[({6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamateas a second intermediate.

The alcohol intermediated was treated with TFA (6 mL) and DCM (6 mL).The mixture was stirred at room temperature for 2 h, and thenconcentrated under reduced pressure. The resulting residue was purifiedby preparative LCMS (Waters SunFire™ C18 column, 19 mm×100 mm, 5 μmparticle size, eluting with a gradient of MeCN/water containing 0.1%NH₄OH, at flow rate of 30 mL/min.) to afford two diastereoisomers of thetitle compound as white powders.

Diastereoisomer 1. First peak. Retention time 1.48 min. LCMS calc. forC₂₈H₃₁F₃N₅O₃(M+H)⁺ m/z=542.2; found: 542.1. ¹H NMR (300 MHz, DMSO-d₆) δ10.72 (s, 1H), 9.40 (s, 1H), 8.31 (m, 1H), 8.17 (m, 1H), 7.26 (d, J=9.0Hz, 2H), 5.23 (m, 1H), 4.75 (m, 1H), 4.51 (s, 2H), 3.34 (s, 3H), 2.99(m, 1H), 2.84 (m, 2H), 2.71 (m, 1H), 2.53 (m, 1H), 2.41 (m, 1H), 2.28(m, 1H), 2.22 (m, 1H), 1.77 (m, 1H), 1.49 (m, 2H), 1.28 (m, 1H), 0.53(d, J=6.0 Hz, 3H) ppm.

Diastereoisomer 2. Second peak: Retention time 1.56 min. LCMS calc. forC₂₈H₃₁F₃N₅O₃(M+H)⁺ m/z=542.2; found: 542.1. ¹H NMR (300 MHz, DMSO-d₆) δ10.71 (s, 1H), 9.40 (s, 1H), 8.31 (m, 1H), 8.17 (m, 1H), 7.26 (d, J=9.0Hz, 2H), 5.24 (m, 1H), 4.78 (m, 1H), 4.51 (s, 2H), 3.34 (s, 3H), 2.97(m, 1H), 2.83 (m, 2H), 2.71 (m, 1H), 2.53 (m, 1H), 2.41 (m, 1H), 2.29(m, 1H), 2.25 (m, 1H), 1.72 (m, 1H), 1.51 (m, 2H), 1.28 (m, 1H), 0.52(d, J=6.6 Hz, 3H) ppm.

The diastereoisomers correspond to the (7R) and (7S) diastereoisomers ofthe title compound.

Example 65N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxamide

Step 1. 1-(3,5-Difluorophenyl)ethanol

To a solution of 3,5-difluorobenzaldehyde (3.00 g, 21.1 mmol) in THF (30mL) at 0-5° C. was added methylmagnesium bromide in THF (3.0 M; 8.44 mL,25.3 mmol) dropwise. The mixture was stirred at 0-5° C. for 1 h,quenched with brine, and then extracted with EtOAc (2 times). Thecombined organic phases were washed with water and brine, dried overNa₂SO₄, and concentrated under reduced pressure to give the sub-titlecompound as a colorless oil (3.02 g, 90.4%). ¹H NMR (300 MHz, CDCl₃) δ6.89 (m, 2H), 6.69 (m, 1H), 4.88 (q, J=6.3 Hz, 1H), 1.47 (d, J=6.3 Hz,3H) ppm.

Step 2. 1-(3, 5-Difluorophenyl)ethanone

Dess-Martin periodinane (9.66 g, 22.8 mmol) was added portionwise to asolution of 1-(3,5-difluorophenyl)ethanol (3.00 g, 19.0 mmol) in DCM (40mL) cooled in an ice bath.

The mixture was stirred at room temperature for 2 h, then concentratedunder reduced pressure. The residue was purified by purified by columnchromatography on silica gel using CombiFlash® apparatus eluting withEtOAc/hexanes (0-40%). The purification gave 2.06 g (69.6%) of thesub-title compound as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.45(m, 2H), 7.01 (m, 1H), 2.59 (s, 3H) ppm.

Step 3. 2-(3,5-Difluorophenyl)propan-2-ol

To a solution of 1-(3,5-difluorophenyl)ethanone (2.00 g, 12.8 mmol) inTHF (20 mL) at 0-5° C., methylmagnesium bromide in THF (3.0 M; 5.12 mL,15.4 mmol) was added dropwise. The mixture was stirred at 0-5° C. for 1h, then quenched with brine, extracted with EtOAc (2 times). Thecombined organic phases were washed with water and brine, dried overNa₂SO₄, and concentrated under reduced pressure to give the sub-titlecompound as a colorless oil (2.12 g, 96.1%).

Step 4. 2-[3, 5-Difluoro-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)phenyl]propan-2-ol

To a mixture of 2-(3,5-difluorophenyl)propan-2-ol (2.00 g, 11.6 mmol) inTHF (46 mL) at −78° C., n-BuLi in hexanes (1.6 M; 18.2 mL, 29.0 mmol)was slowly added through a dripping funnel. When the addition wascomplete, the mixture was kept at −78° C. for 1 h.2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.11 mL, 34.8mmol) was then added in one portion. The mixture was allowed to warm uproom temperature and stirred for 1 h, then the reaction was quenchedwith water and the solution was extracted with EtOAc. The combinedorganic extracts were washed with brine, dried over Na₂SO₄, andconcentrated under reduced pressure to give the sub-title compound as acolorless oil. LCMS calc. for C₁₅H₂₁BF₂O₃Na (M+Na)⁺ m/z=321.2; found:321.0.

Step 5. Methyl6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxylate

To a nitrogen purged mixture of2-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propan-2-ol(1.53 g, 5.13 mmol), methyl 6-bromo-5-fluoropyridine-2-carboxylate (1.20g, 5.13 mmol) and DIPEA (2.7 mL, 15 mmol) in 1,4-dioxane (20 mL) andwater (1.2 mL), bis(tri-tert-butylphosphine)palladium (262 mg, 0.513mmol) was added. The reaction mixture was heated at 120° C. for 40 min.,then cooled and filtered through a pad of diatomaceous earth. Thefiltrate was concentrated under reduced pressure. The crude residue waspurified by silica gel column chromatography (0-50% EtOAc in hexanes) togive methyl6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxylateas a white powder, which was used without further purification.

Step 6.6-[2,6-Difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxylicacid

The methyl6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxylateprepared as described in Step 5 was treated with THF (8 mL), MeOH (8 mL)and 1.0 M aq. NaOH (8 mL, 8 mmol) at room temperature for 1 h. Thevolatile solvents were removed under reduced pressure. The residue wasneutralized to pH around 6-7 with 1 M HCl. The precipitates werefiltered, rinsed with water and dried to give the sub-title compound asa white solid (0.332 g, 20.8%). LCMS calc. for C₁₅H₁₃F₃NO₃ (M+H)⁺m/z=312.1; found: 312.1.

Step 7. N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxamide

A mixture of tert-butyl((3R,4R,5S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(200 mg, 0.418 mmol),6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxylicacid (130 mg, 0.418 mmol), HATU (318 mg, 0.836 mmol) in DMF (1.5 mL) andDIPEA (218 μL, 1.25 mmol) was stirred at room temperature for 2 h. Afterquenched with water, the mixture was extracted with EtOAc (2×). Thecombined organic phases were washed with brine, dried over Na₂SO₄, andconcentrated. The residue was purified by purified by columnchromatography on silica gel using CombiFlash® apparatus eluting withEtOAc/hexanes (50-100%), to yield an amide intermediate, tert-butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-{5-[({6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-2,3-dihydrofuro[2,3-b]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate.

The amide intermediate prepared as described above was treated with 4.0M HCl in dioxane (8 mL, 30 mmol) at room temperature overnight. Thereaction mixture was concentrated under reduced pressure. The resultingresidue was purified by preparative LCMS (Waters SunFire™ C18 column, 19mm×100 mm, 5 μm particle size, eluting with a gradient of MeCN/watercontaining 0.1% NH₄OH, at flow rate of 30 mL/min.) to give the titlecompound as a white powder. LCMS calc. for C₂₈H₃₁F₃N₅O₄(M+H)⁺ m/z=558.2;found: 558.0. ¹H NMR (300 MHz, DMSO-d₆) δ 10.17 (s, 1H), 8.69 (s, 1H),8.32 (m, 1H), 8.16 (m, 1H), 7.32 (d, J=9.0 Hz, 2H), 5.27 (br s, 1H),4.49 (m, 3H), 3.05 (m, 1H), 2.96 (m, 1H), 2.66-2.42 (m, 5H), 1.47 (s,6H), 0.68 (d, J=6.6 Hz, 3H) ppm.

Example 66N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridine-2-carboxamide

A mixture of3-amino-4-((3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (324 mg, 0.606 mmol),6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridine-2-carboxylicacid (180 mg, 0.606 mmol) and HATU (0.460 g, 1.21 mmol) in DMF (3.0 mL)and DIPEA (0.316 mL, 1.82 mmol) was stirred at room temperature for 2 h.After quenching the reaction with water, the mixture was extracted withEtOAc (2 times). The combined organic extracts were washed with brine,dried over Na₂SO₄, and concentrated under reduced pressure. The residuewas purified by purified by column chromatography on silica gel usingCombiFlash® apparatus eluting with EtOAc/hexanes (50-100%) to give anamide intermediate,4-((3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-1-yl)-3-[({6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate.

To the amide intermediate prepared as described above THF (5 mL), MeOH(5 mL) and 1.0 M aq. NaOH (5 mL, 5 mmol) were added. The mixture wasstirred at room temperature for 20 min. The volatile organic solventswere removed under reduced pressure. The residue was extracted withEtOAc (2 times). The combined organic phases were then washed withbrine, dried over Na₂SO₄, and concentrated under reduced pressure togive an alcohol intermediate, tert-butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-{3-[({6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate.

The alcohol intermediate prepared as described above was treated with4.0 M HCl in dioxane (10 mL, 40 mmol) at room temperature overnight. Thereaction mixture was concentrated under reduced pressure. The residuewas purified by preparative LCMS (Waters SunFire™ C18 column, 19 mm×100mm, 5 μm particle size, eluting with a gradient of MeCN/water containing0.1% NH₄OH, at flow rate of 30 mL/min.) to afford two diastereoisomersof the title compound as white powders.

Diastereoisomer 1. First peak. Retention time: 1.452 min. LCMS calc. forC₂₈H₃₁F₃N₅O₄(M+H)⁺ m/z=558.2; found: 558.0. ¹H NMR (400 MHz, DMSO-d₆) δ10.53 (s, 1H), 9.32 (s, 1H), 8.35 (m, 1H), 8.19 (m, 1H), 7.20 (d, J=10.2Hz, 2H), 5.29 (m, 1H), 4.82 (m, 1H), 4.52 (s, 2H), 4.49 (m, 1H), 3.35(s, 3H), 3.04 (m, 1H), 2.92 (m, 1H), 2.84 (m, 2H), 2.71 (m, 1H), 2.60(m, 1H), 2.57 (m, 1H), 2.43 (m, 1H), 2.29 (m, 1H), 1.78 (m, 1H), 1.45(m, 2H), 0.68 (d, J=6.4 Hz, 3H) ppm.

Diastereoisomer 2. Second peak. Retention time: 1.563 min. LCMS calc.for C₂₈H₃₁F₃N₅O₄(M+H)⁺ m/z=558.2; found: 558.0. ¹H NMR (400 MHz,DMSO-d₆) δ 10.54 (s, 1H), 9.33 (s, 1H), 8.35 (m, 1H), 8.19 (m, 1H), 7.19(d, J=8.8 Hz, 2H), 5.28 (m, 1H), 4.80 (m, 1H), 4.52 (s, 2H), 4.49 (m,1H), 3.35 (s, 3H), 3.04 (m, 1H), 2.93 (m, 1H), 2.84 (m, 2H), 2.70 (m,1H), 2.60 (m, 1H), 2.56 (m, 1H), 2.43 (m, 1H), 2.26 (m, 1H), 1.79 (m,1H), 1.44 (m, 2H), 0.69 (d, J=6.4 Hz, 3H) ppm.

The diastereoisomers correspond to the (7R) and (7S) diastereoisomers ofthe title compound.

Example 67N-{4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxamide

A mixture of3-amino-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (299 mg, 0.739 mmol),6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxylicacid (230 mg, 0.739 mmol) and HATU (562 mg, 1.48 mmol) in DMF (0.7 mL)and DIPEA (0.386 mL, 2.22 mmol) was stirred at room temperature for 2 h.The reaction mixture was quenched with water, the mixture was extractedwith EtOAc (2 times). The combined organic phases were washed withbrine, dried over Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by purified by column chromatography on silica gelusing CombiFlash® apparatus eluting with EtOAc/hexanes (50-100%) to givean amide intermediate,4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-3-[({6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate.

The amide intermediate prepared as described above was treated with THF(6 mL), MeOH (6 mL) and 1.0 M aq. NaOH (7.39 mL, 7.39 mmol) at roomtemperature for 20 min. The volatile solvents were removed under reducedpressure. The residue was extracted with EtOAc (2 times). The combinedorganic phases were washed with brine, dried over Na₂SO₄, concentratedunder reduced pressure to give an alcohol intermediate, tert-butyl((3S,5R)-1-{3-[({6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate.

The alcohol intermediate prepared as described above was treated withTFA (6 mL) and DCM (6 mL). The solution was stirred at room temperaturefor 2 h, concentrated. The residue was purified by prep. LCMS (WatersSunFire™ C18 column, 19 mm×100 mm, 5 μm particle size, eluting with agradient of MeCN/water containing 0.1% NH₄OH, at flow rate of 30mL/min.) to provide two diastereoisomers as white powders.

Diastereoisomer 1. First peak. Retention time: 1.505 min. LCMS calc. forC₂₉H₃₃F₃N₅O₃(M+H)⁺ m/z=556.3; found: 556.0. ¹H NMR (400 MHz, DMSO-d₆) δ10.77 (s, 1H), 9.46 (s, 1H), 8.36 (m, 1H), 8.21 (m, 1H), 7.41 (d, J=10.2Hz, 1H), 5.47 (m, 1H), 5.30 (m, 1H), 4.84 (m, 1H), 3.01 (m, 1H), 2.92(m, 1H), 2.84 (m, 1H), 2.78 (m, 1H), 2.63 (m, 1H), 2.51 (m, 1H), 2.33(m, 1H), 2.30 (m, 1H), 1.77 (m, 1H), 1.59 (m, 1H), 1.50 (s, 6H), 1.37(m, 1H), 0.56 (d, J=6.4 Hz, 3H) ppm.

Diastereoisomer 2. Second peak. Retention time: 1.599 min. LCMS calc.for C₂₉H₃₃F₃N₅O₃(M+H)⁺ m/z=556.3; found: 556.0. ¹H NMR (400 MHz,DMSO-d₆) δ 10.79 (s, 1H), 9.46 (s, 1H), 8.35 (m, 1H), 8.21 (m, 1H), 7.40(d, J=8.8 Hz, 2H), 5.47 (m, 1H), 5.28 (m, 1H), 4.80 (m, 1H), 3.05 (m,1H), 2.90 (m, 1H), 2.84 (m, 1H), 2.75 (m, 1H), 2.61 (m, 1H), 2.46 (m,1H), 2.32 (m, 1H), 2.26 (m, 1H), 1.81 (m, 1H), 1.56 (m, 1H), 1.50 (s,6H), 1.35 (m, 1H), 0.57 (d, J=6.4 Hz, 3H) ppm.

The diastereoisomers correspond to the (7R) and (7S) diastereoisomers ofthe title compound.

Example 68N-{4-[(3R,4R,5S)-3-Amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

Step 1. tert-Butyl(4R)-4-{(1R,2R)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2-cyclopropyl-1-hydroxy-3-oxopropyl}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate

To a −40° C. solution of(4R)-4-benzyl-3-(cyclopropylacetyl)-1,3-oxazolidin-2-one (2.0 g, 7.7mmol) in anhydrous DCM (45 mL), a solution of 1.0 M titaniumtetrachloride in DCM (9.3 mL) was added drop-wise under an atmosphere ofnitrogen to form a yellow slurry. After 10 min., DIPEA (3.36 mL, 19.3mmol) was added drop-wise, changing the color from yellow to deeppurple. The reaction mixture was allowed to warm gradually to −20° C.while stirring over 1 h. The reaction mixture was again cooled to −40°C., and a solution of tert-butyl(4R)-4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (1.8 g, 7.85mmol) (Aldrich) in anhydrous DCM (5 mL) was added drop-wise. Thereaction mixture was allowed to warm gradually to 0° C. over 1 h andthen allowed to stir for an additional 1.5 h at 0° C. The reaction wasquenched by the addition of saturated NH₄Cl (aq.) (15 mL). Afterseparation of the two layers that resulted, the organic layer was washedwith water and brine, dried over Na₂SO₄, concentrated under reducedpressure and purified by flash chromatography (120 g silica gel, elutingwith 0-60% EtOAc/hexanes) to afford the sub-title compound (1.9 g, 50%).LC/MS (ESI) m/z calc. for C₂₆H₃₆N₂O₇Na: 511.2 [M+Na]⁺, found 511.1.

Step 2. tert-Butyl(4R)-4-((1R,2R)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-1-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclopropyl-3-oxopropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate

To a −40° C. solution of tert-butyl(4R)-4-{(1R,2R)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2-cyclopropyl-1-hydroxy-3-oxopropyl}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate(1.80 g, 3.68 mmol) in anhydrous DCM (10 mL), 2,6-lutidine (0.85 mL, 7.3mmol) was added under an atmosphere of nitrogen. After 10 min., asolution of tert-butyldimethylsilyl trifluoromethanesulfonate (1.1 mL,4.9 mmol) in anhydrous DCM (1 mL) was added. The reaction mixture wasallowed to warm gradually to ambient temperature while stirringovernight. The crude reaction mixture was diluted with1,2-dichloroethane and cooled to 0° C. prior to quenching with saturatedNaHCO₃ (aq.). Upon separation of the two layers that resulted, theorganic layer was washed with water and brine, dried over Na₂SO₄,concentrated under reduced pressure and purified by flash chromatography(120 g silica gel, eluting with 0-30% EtOAc/hexanes) to afford thesub-title compound (2.1 g, 95%). LC/MS (ESI) m/z calc. forC₃₂H₅₀N₂O₇SiNa: 625.3 [M+Na]⁺, found 625.1.

Step 3. tert-Butyl(4R)-4-((1R,2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclopropyl-3-hydroxypropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate

A solution of tert-butyl(4R)-4-((1R,2R)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-1-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclopropyl-3-oxopropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate(3.3 g, 5.5 mmol) in anhydrous THF (50 mL) and EtOH (1 mL) was cooled to−30° C. prior to the addition of lithium tetrahydroborate (0.24 g, 11mmol) under an atmosphere of nitrogen. The reaction mixture was allowedto gradually warm to ambient temperature while stirring for 20 h. Thecrude reaction mixture was diluted with diethyl ether (36 mL) and cooledto 0° C. prior to the addition of 1 M NaOH (aq.) (36 mL). Uponseparation of the layers that resulted, the aqueous layer was extractedwith EtOAc several times and the combined organic extracts were washedwith brine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The crude product was purified by flash column chromatography(120 g silica gel, eluting with 0-40% EtOAc/hexanes) to afford thesub-title compound (1.27 g, 54%). LC/MS (ESI) m/z calc. forC₂₂H₄₃NO₅SiNa: 452.3 [M+Na]⁺, found 452.0.

Step 4. tert-Butyl(4R)-4-((1R,2S)-3-azido-1-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclopropylpropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate

To a solution of tert-butyl(4R)-4-((1R,2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclopropyl-3-hydroxypropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate(1.3 g, 3.0 mmol) and triphenylphosphine (1.6 g, 6.1 mmol) in anhydrousTHF (20 mL), DIAD (1.2 mL, 5.9 mmol) was added drop-wise under anatmosphere of nitrogen. Upon completion of addition, a precipitate wasformed. The reaction mixture was stirred for 30 min. thendiphenylphosphonic azide (1.3 mL, 6.2 mmol) in anhydrous THF (1.0 mL)was added. After stirring at ambient temperature for 3 h, the volatileorganic solvents were removed under reduced pressure and the crudeproduct was purified by flash column chromatography (120 g of silicagel, eluting with 0-15% EtOAc-hexanes) to afford the sub-title compoundas a light yellow oil (1.18 g, 86%). LC/MS (ESI) m/z calc. forC₁₇H₃₅N₄O₂Si: 355.30 [M-Boc+H]⁺, found: 355.1.

Step 5. tert-Butyl(2R,3R,4S)-5-azido-4-cyclopropyl-1,3-dihydroxypentan-2-ylcarbamate

A solution of tert-butyl(4R)-4-((1R,2S)-3-azido-1-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclopropylpropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate(1.16 g, 2.55 mmol) in MeOH (5 mL) was cooled on an ice bath, then TFA(4.9 mL, 64 mmol) was added. The reaction mixture was allowed to warm toambient temperature and stirred for 30 min. The volatile organicsolvents were removed under reduced pressure and the residue wasazeotropically evaporated with toluene several times. The residue wasthen dissolved in anhydrous DCM (18 mL) and DIPEA (0.99 g, 7.6 mmol) anddi-tert-butyl dicarbonate (0.84 g, 3.8 mmol) were added. The solutionwas stirred at ambient temperature for 4 h. The crude reaction mixturewas concentrated under reduced pressure and the residue was purified byflash column chromatography (40 g silica gel, eluting with 0-100%EtOAc/DCM) to afford the desired product (0.33 g, 43%) and tert-butyl[(1R,2R,3S)-4-azido-2-{[tert-butyl(dimethyl)silyl]oxy}-3-cyclopropyl-1-(hydroxymethyl)butyl]carbamate(0.50 g, 50%). LCMS (ESI) calc. for C₁₃H₂₅N₄O₄ [M+H]⁺ m/z=301.2, found:301.2. For tert-butyl[(1R,2R,3S)-4-azido-2-{[tert-butyl(dimethyl)silyl]oxy}-3-cyclopropyl-1-(hydroxymethyl)butyl]carbamate:LCMS (ESI) calc. for C₁₉H₃₈N₄O₄SiNa [M+Na]⁺ m/z=437.3, found 437.0.

Step 6.(2R,3R,4S)-5-Azido-2-[(tert-butoxycarbonyl)amino]-4-cyclopropyl-3-hydroxypentyl4-methylbenzenesulfonate

To a solution of tert-butyl[(1R,2R,3S)-4-azido-3-cyclopropyl-2-hydroxy-1-(hydroxymethyl)butyl]carbamate(0.435 g, 1.45 mmol) in anhydrous pyridine (5 mL) was added4-dimethylaminopyridine (0.055 g, 0.20 mmol) and para-toluenesulfonylchloride (0.55 g, 2.8 mmol). After stirring at ambient temperature for 2h, the reaction mixture was diluted with EtOAc (40 mL) and H₂O (3 mL).The layers were separated, the organic layer was washed with H₂O (3×3mL) and the combined aqueous phases were extracted with EtOAc (3 mL).The combined organic layers were washed with brine (3 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The crudeproduct was purified by flash column chromatography (40 g silica gelcolumn, eluting with 0-30% EtOAc/hexanes) to afford the sub-titlecompound (506 mg, 77%). LCMS (ESI) calc. for C₁₅H₂₃N₄O₄S[M+H-Boc+H]+m/z=355.2, found 355.1.

Step 7. tert-Butyl[(3R,4R,5S)-5-cyclopropyl-4-hydroxypiperidin-3-yl]carbamate

A mixture of(2R,3R,4S)-5-azido-2-[(tert-butoxycarbonyl)amino]-4-cyclopropyl-3-hydroxypentyl4-methylbenzenesulfonate (0.506 g, 1.11 mmol), DIPEA (0.31 mL, 1.8mmol), and 10% palladium (dry basis) on activated carbon (wet, Degussatype E101 NE/W) (0.1 g) in MeOH (5 mL) was stirred under an atmosphereof hydrogen introduced via a balloon. After 3 h, the crude reactionmixture was filtered through a pad of diatomaceous earth and the solidswere washed thoroughly with MeOH. The volatile organic solvents wereremoved under reduced pressure and the residue was dried under highvacuum to afford the sub-title compound as a solid. The crude productwas used directly in the subsequent displacement reaction withoutfurther purification. LCMS (ESI) m/z calc. for C₁₃H₂₅N₂O₃ 257.2 [M+H]⁺,found 257.2.

Step 8. tert-Butyl[(3R,4R,5S)-5-cyclopropyl-4-hydroxy-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate

A mixture of 4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine(0.094 g, 0.47 mmol), tert-butyl[(3R,4R,5S)-5-cyclopropyl-4-hydroxypiperidin-3-yl]carbamate (0.13 g,0.51 mmol), and triethylamine (0.26 mL, 1.9 mmol) in isopropyl alcohol(2 mL) was heated at 90° C. for 2 days. The desired product partiallyprecipitated from the reaction mixture and was collected by filtration,washed with hexanes and dried under reduced pressure to afford puresub-title compound (0.080 g). The filtrate was concentrated underreduced pressure and purified by flash column chromatography (20 gsilica gel column, eluting with 0-15% MeOH/DCM) to afford furthersub-title compound (0.034 g, total 0.114 g, 58%). LCMS (ESI) m/z calc.for C₂₁H₃₁N₄O₅ 419.2 [M+H]⁺, found 419.1.

Step 9. tert-Butyl[(3R,4R,5S)-5-cyclopropyl-4-hydroxy-1-(3-nitro-1-oxido-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate

A solution of tert-butyl[(3R,4R,5S)-5-cyclopropyl-4-hydroxy-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate(0.113 g, 0.270 mmol) in anhydrous DCM (2.5 mL) was cooled to 0° C. andmCPBA (0.080 g, 0.33 mmol, 4×0.020 g) was added portion-wise. After 15min., the reaction mixture was allowed to warm to ambient temperatureand was stirred for 2 h. The reaction was quenched by the addition of asolution of Na₂S₂O₃ (0.051 g, 0.32 mmol) in water (1 mL) followed by 4 Maq. NaOH (1 mL). The layers were separated and the organic fraction wasconcentrated and purified by flash column chromatography (20 g silicagel column, eluting with 0-30% MeOH/EtOAc) to afford the sub-titlecompound (0.050 g, 43%). LCMS (ESI) m/z calc. for C₂₁H₃₁N₄O₆ 435.2[M+H]⁺, found 435.0.

Step 10.4-{(3R,4R,5S)-4-(Acetyloxy)-3-[(tert-butoxycarbonyl)amino]-5-cyclopropylpiperidin-1-yl}-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylAcetate

Ac₂O (1.30 mL, 13.8 mmol) was added to tert-butyl[(3R,4R,5S)-5-cyclopropyl-4-hydroxy-1-(3-nitro-1-oxido-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate(0.050 g, 0.12 mmol) and the resulting solution was heated at 90° C. ina sealed vial for 16 h. The volatiles were removed under reducedpressure and the residue was dissolved in EtOAc and cooled to 0° C. andsaturated aq.NaHCO₃ was added. After stirring for 15 min., the layerswere separated and the organic fraction was washed with brine, driedover Na₂SO₄, filtered and concentrated under reduced pressure to affordthe sub-title compound (0.055 g, 92%), which was used without furtherpurification in the subsequent reaction. LCMS (ESI) m/z calc. forC₂₅H₃₅N₄O₈ 519.2 [M+H]⁺, found 519.1.

Step 11.(3R,4R,5S)-1-[7-(Acetyloxy)-3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-3-[(tert-butoxycarbonyl)amino]-5-cyclopropylpiperidin-4-ylAcetate

A solution of4-{(3R,4R,5S)-4-(acetyloxy)-3-[(tert-butoxycarbonyl)amino]-5-cyclopropylpiperidin-1-yl}-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (0.055 g, 0.11 mmol) in MeOH (5.0 mL) and EtOAc (1.0 mL) wasdeoxygenated and purged with nitrogen prior to the addition of 10%palladium (dry basis) on activated carbon (wet, Degussa type E101 NE/W)(0.025 g). The reaction mixture was stirred under an atmosphere ofhydrogen, introduced via a balloon, for 2 h. The crude reaction mixturewas filtered through a pad of diatomaceous earth and the solids werewashed thoroughly with EtOAc and MeOH. The filtrate was concentratedunder reduced pressure to afford the sub-title compound (0.052 g, 100%).LCMS (ESI) m/z calc. for C₂₅H₃₇N₄O₆ 489.3 [M+H]+, found 489.0.

Step 12.N-{4-[(3R,4R,5S)-3-Amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

To a mixture of 6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylicacid (0.028 g, 0.11 mmol), HATU (0.056 g, 0.15 mmol) and DIPEA (0.051mL, 0.29 mmol) in 1,2-dichloroethane (0.4 mL) was added a solution of(3R,4R,5S)-1-[7-(acetyloxy)-3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-3-[(tert-butoxycarbonyl)amino]-5-cyclopropylpiperidin-4-ylacetate (0.050 g, 0.10 mmol) in 1,2-dichloroethane (0.5 mL). Thereaction mixture was stirred at 45° C. for 1 h and then at ambienttemperature overnight. The reaction mixture was diluted with EtOAc (40mL) and H₂O (3 mL). The layers were separated and the organic layer waswashed with H₂O (3×3 mL). The combined aqueous phases were extractedwith EtOAc (3 mL). The combined organic extracts were washed with brine(3 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The crude product was dissolved in THF (1.3 mL) and MeOH (0.4mL) and to this was added 1 M aq. NaOH (1 mL) and the resulting mixturewas stirred for 2.5 h at ambient temperature. The reaction mixture wasdiluted with EtOAc (40 mL) and neutralized by the addition of 1 M aq.HCl to adjust the pH to ˜7. The layers were separated, the organic layerwas washed with H₂O (3×3 mL) and the combined aqueous phases wereextracted with EtOAc (3 mL). The combined organic extracts were washedwith brine (3 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure. The crude product was dissolved in 4 M HCl in1,4-dioxane (2 mL) and stirred at ambient temperature for 30 min. Thevolatile organic solvents were removed under reduced pressure and theresidue was re-dissolved in MeOH (5 mL) and neutralized by the additionof saturated NH₄OH. The crude reaction mixture was purified by masstriggered preparative-HPLC (Waters SunFire™ C18 column, 19 mm×100 mm, 5μm particle size, eluting with a gradient of MeCN/water containing 0.1%NH₄OH, at flow rate of 30 mL/min.) to afford the two 7-hydroxyldiastereoisomers of the title compound as two peaks.

Diastereoisomer 1. First peak (12.4 mg). Retention time 1.09 min., LCMS(ESI) m/z calc. for C₂₈H₂₉F₃N₅O₃ 540.2 [M+H]⁺, found 540.0.

Diastereoisomer 2. Second peak (10.4 mg) Retention time 1.16 min, LCMS(ESI) m/z calc. for C₂₈H₂₉F₃N₅O₃ 540.2 [M+H]⁺, found 540.0.

The diastereoisomers correspond to the (7R) and (7S) diastereoisomers ofthe title compound.

Example 69N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-[2,6-difluoro-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]-5-fluoropyridine-2-carboxamide

Step 1. 3-(3,5-Difluorophenoxy)tetrahydro-2H-pyran

A solution of 3,5-difluorophenol (1.15 g, 8.81 mmol),tetrahydro-2H-pyran-3-ol (0.900 g, 8.81 mmol), triphenylphosphine (2.31g, 8.81 mmol) and DIAD (1.74 mL, 8.81 mmol) in THF (10 mL) was stirredovernight. The solution was then concentrated under reduced pressure andthe residue was purified by purified by column chromatography on silicagel using CombiFlash® apparatus eluting with EtOAc/hexanes (0-30%). Thepurification afforded 1.43 g (75.8%) of the sub-title compound as acolorless oil.

Step 2. 3-[3, 5-Difluoro-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)phenoxy]tetrahydro-2H-pyran

To a mixture of 3-(3,5-difluorophenoxy)tetrahydro-2H-pyran (1.42 g, 6.63mmol) in THF (26 mL) at −78° C., a solution of n-BuLi in hexanes (1.6 M;10.4 mL, 16.6 mmol) was added slowly through a dripping funnel. Whenaddition was complete, the mixture was kept at −78° C. for 1 h.2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.06 mL, 19.9mmol) was then added in one portion. The mixture was allowed to warm toroom temperature and stirred for 1 h. The mixture was quenched withNaHCO₃ solution and extracted with EtOAc. The organic extract was washedwith brine, dried over Na₂SO₄, and concentrated under reduced pressureto give sub-title compound as a colorless oil. LCMS calc. forC₁₇H₂₄BF₂O₄(M+H)⁺ m/z=341.2; found: 341.1.

Step 3.6-[2,6-Difluoro-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]-5-fluoropyridine-2-carboxylicacid

A mixture of3-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]tetrahydro-2H-pyran(0.436 g, 1.28 mmol), methyl 6-bromo-5-fluoropyridine-2-carboxylate(0.300 g, 1.28 mmol) and DIPEA (0.67 mL, 3.8 mmol) in 1,4-dioxane (6 mL)and water (0.3 mL) was purged with nitrogen and thenbis(tri-tert-butylphosphine)palladium (65.5 mg, 0.128 mmol) was added.The reaction mixture was sealed and heated at 120° C. for 40 min., thencooled and filtered through a pad of diatomaceous earth. The filtratewas concentrated under reduced pressure and the resulting residue waspurified by silica gel column chromatography (0-50% EtOAc in hexanes) togive methyl6-[2,6-difluoro-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]-5-fluoropyridine-2-carboxylate.

The methyl6-[2,6-difluoro-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]-5-fluoropyridine-2-carboxylatewas treated with THF (2 mL), MeOH (2 mL) and 1.0 M aq. NaOH (2 mL, 2mmol) at room temperature for 1 h. The volatile organic solvents wereremoved and the residue was neutralized to pH-5-6 with 1 M HCl. Thesolid that precipitated was filtered, rinsed with water, and dried togive sub-title compound as a white solid. LCMS calc. for C₁₇H₁₅F₃NO₄(M+H)⁺ m/z=354.1; found: 353.9.

Step 4. N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-[2,6-difluoro-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]-5-fluoropyridine-2-carboxamide

A mixture of tert-butyl((3R,4R,5S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(20 mg, 0.042 mmol),6-[2,6-difluoro-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]-5-fluoropyridine-2-carboxylicacid (18 mg, 0.050 mmol) and HATU (32 mg, 0.084 mmol) in DMF (0.10 mL)and DIPEA (22 μL, 0.13 mmol) was stirred at room temperature for 2 h.The reaction was quenched with water and the mixture was extracted withEtOAc (2×). The combined organic extracts were washed with brine, driedover Na₂SO₄, and concentrated under reduced pressure. The residue waspurified by purified by column chromatography on silica gel usingCombiFlash® apparatus eluting with EtOAc/hexanes (50-100%) to yield theamide intermediate, tert-butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-{5-[({6-[2,6-difluoro-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-2,3-dihydrofuro[2,3-b]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate.

The amide intermediate prepared as described above was treated with 4.0M HCl in dioxane (1 mL, 4 mmol) at room temperature overnight. Thesolution was then concentrated and the residue was purified bypreparative LCMS (Waters SunFire™ C18 column, 19 mm×100 mm, 5 μmparticle size, eluting with a gradient of MeCN/water containing 0.1%NH₄OH, at flow rate of 30 mL/min.) to afford a mixture ofdiastereoisomers of the title compound (S) and (R) configuration of thetetrahydropyran) as a white powder. LCMS calc. for C₃₀H₃₃F₃N₅O₅(M+H)⁺m/z=600.2; found: 600.2. ¹H NMR (300 MHz, DMSO-d₆) δ 10.15 (s, 1H), 8.70(m, 1H), 8.24 (dd, J=8.7 and 4.2 Hz, 1H), 8.09 (dd, J=8.7 and 8.7 Hz,1H), 6.87 (d, J=10.2 Hz, 2H), 4.46 (m, 4H), 3.78 (m, 1H), 3.52 (m, 3H),3.31 (m, 1H), 3.16 (m, 1H), 3.00 (m, 1H), 2.90 (m, 1H), 2.52 (m, 2H),1.99 (m, 1H), 1.72 (m, 2H), 1.43 (m, 3H), 0.65 (2 d, 3H) ppm.

Example 70N-{4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]-5-fluoropyridine-2-carboxamide

A mixture of3-amino-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (30 mg, 0.074 mmol),6-[2,6-difluoro-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]-5-fluoropyridine-2-carboxylicacid (26 mg, 0.074 mmol) and HATU (56 mg, 0.15 mmol) in DMF (0.3 mL) andDIPEA (39 μL, 0.22 mmol) was stirred at room temperature for 2 h. Thereaction mixture was quenched with water and the resulting mixture wasextracted with EtOAc (2 times). The combined organic phases were washedwith brine, dried over Na₂SO₄ and concentrated under reduced pressure.The residue was purified by purified by column chromatography on silicagel using CombiFlash® apparatus eluting with EtOAc/hexanes (50-100%) toafford an amide intermediate,4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-3-[({6-[2,6-difluoro-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate.

The amide intermediate was treated with THF (0.7 mL), MeOH (0.7 mL) and1.0 M aq. NaOH (0.74 mL, 0.74 mmol) at room temperature for 20 min. Thevolatile organic solvents were removed. The residue was extracted withEtOAc (2 times). The combined organic extracts were washed with brine,dried over Na₂SO₄, and concentrated to give an alcohol intermediate,tert-butyl((3S,5R)-1-{3-[({6-[2,6-difluoro-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate.

The alcohol intermediate made above was treated with 4.0 M HCl indioxane (1 mL, 5 mmol) at room temperature overnight. The solution wasconcentrated under reduced pressure and the resulting residue waspurified by preparative LCMS (Waters SunFire™ C18 column, 19 mm×100 mm,5 μm particle size, eluting with a gradient of MeCN/water containing0.1% NH₄OH, at flow rate of 30 mL/min.) to give two separateddiastereoisomers of the title compound as white powders.

Diastereoisomer 1. First peak. Retention time: 1.204 min. LCMS calc. forC₃₁H₃₅F₃N₅O₄(M+H)⁺ m/z=598.3; found: 598.0.

Diastereoisomer 2. Second peak. Retention time: 1.283 min. LCMS calc.for C₃₁H₃₅F₃N₅O₄(M+H)⁺ m/z=598.3; found: 598.0.

The diastereoisomers are tentatively assigned as the separated (7R) and(7S) diastereoisomers of the title compound, each being a mixture ofdiastereoisomers having (R) and (S) configuration of tetrahydropyranring.

Example 713-Amino-N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

A mixture of tert-butyl((3R,4R,5S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(62 mg, 0.13 mmol),3-[(tert-butoxycarbonyl)amino]-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylicacid (48 mg, 0.13 mmol) and HATU (99 mg, 0.26 mmol) in DMF (0.20 mL, 2.6mmol) and DIPEA (68 μL, 0.39 mmol) was stirred at room temperature for 2h. The reaction was quenched with water, and the mixture was extractedwith EtOAc (2 times). The combined organic phases were washed withbrine, dried over Na₂SO₄, and concentrated under reduced pressure. Theresidue was purified by purified by column chromatography on silica gelusing CombiFlash® apparatus eluting with EtOAc/hexanes (50-100%) togenerate an amide intermediate, tert-butyl[2-({[4-((3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-1-yl)-2,3-dihydrofuro[2,3-b]pyridin-5-yl]amino}carbonyl)-6-(2,6-difluorophenyl)-5-fluoropyridin-3-yl]carbamate.

The amide intermediate prepared as described above was treated with 4.0M HCl in dioxane (2 mL, 8 mmol) at room temperature overnight. Thesolution was concentrated under reduced pressure, and the residue waspurified by preparative LCMS (Waters SunFire™ C18 column, 19 mm×100 mm,5 μm particle size, eluting with a gradient of MeCN/water containing0.1% NH₄OH, at flow rate of 30 mL/min.) to afford the desired product asa white powder. LCMS calc. for C₂₅H₂₆F₃N₆O₃(M+H)⁺ m/z=515.2; found:515.0. ¹H NMR (400 MHz, DMSO-d₆) δ 9.98 (s, 1H), 8.67 (s, 1H), 7.52 (m,1H), 7.39 (br s, 2H), 7.20 (s, 2H), 7.18 (m, 2H), 4.46 (m, 2H), 4.41 (m,1H), 3.02 (m, 1H), 2.90 (m, 1H), 2.59 (m, 1H), 2.52 (m, 1H), 2.37 (m,1H), 1.47 (m, 2H), 1.35 (m, 1H), 0.68 (d, J=6.8 Hz, 3H) ppm.

Example 72N-{4-[(3S,5R)-3-Amino-5-(trifluoromethyl)piperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxamide

Step 1. tert-Butyl[1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate

A mixture of 4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.34g, 1.7 mmol), cis-tert-butyl[5-(trifluoromethyl)piperidin-3-yl]carbamate (0.50 g, 1.9 mmol) inisopropyl alcohol (1.0 g) and DIPEA (1.0 mL, 5.7 mmol) was stirred at110° C. for 2 h. The solution was allowed to cool to room temperature,then the mixture was concentrated under reduced pressure. The residuewas purified by purified by column chromatography on silica gel usingCombiFlash® apparatus (40 g column, eluting with 0 to 70% EtOAc inhexanes) to give the sub-title compound as a pale yellow powder (0.37 g,50%). LCMS calc. for C₁₉H₂₆F₃N₄O₄(M+H)⁺ m/z=431.2; found: 431.0. Thematerial was subjected to chiral HPLC (Phenomenex Lux® Cellulose 4column, 21, 2×250 mm, 5 micron particle size; Mobile phase: 7% EtOH inhexanes; Flow rate: 18 mL/min. isocratic; Column loading: 10mg/injection; Run time: 24 minutes) to give two separated enantiomers ofthe sub-title compound.

Enantiomer 1. First peak. Retention time 16.2 min.

Enantiomer 2. Second peak. Retention time 19.1 min.

Enantiomer 1 is tentatively assigned as tert-butyl[(3R,5S)-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamateand enantiomer 2 is tentatively assigned as the tert-butyl[(3S,5R)-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate.

Step 2. tert-Butyl[(3S,5R)-1-(3-nitro-1-oxido-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate

mCPBA (0.16 g, 0.93 mmol) was added to a solution of tert-butyl[(3S,5R)-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate(0.16 g, 0.37 mmol) (second peak, pure product resolved on chiral HPLCfrom previous step) in DCM (2.0 mL) at room temperature. The reactionmixture was stirred at room temperature for 2 h. The mixture was treatedwith aq. Na₂S₂O₃, then 1 M NaOH, and extracted with EtOAc. The combinedorganic layers were concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel using CombiFlash®apparatus (20 g column) eluting with 0-100% EtOAc in hexanes followed byMeOH/EtOAc (0-30%) to give 0.10 g (60%) of the sub-title compound as areddish solid. 0.033 g of unreacted starting material was recovered.LCMS calc. for C₁₉H₂₆F₃N₄O₅(M+H)+m/z=447.2; found: 446.9.

Step 3.4-[(3S,5R)-3-[(tert-Butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylAcetate

A mixture of tert-butyl[(3S,5R)-1-(3-nitro-1-oxido-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate(0.100 g, 0.224 mmol) in Ac₂O (1.5 mL, 16 mmol) was stirred at 90° C.for 1 h. The solution was allowed to cool to room temperature, thenconcentrated under reduced pressure at 60° C. The residue was dilutedwith EtOAc (5 mL), washed quickly with 1N NaOH. The aqueous phase wasextracted with EtOAc twice. The combined organic phases were condensedand columned on 20 g silica gel, eluting with 0-50% EtOAc in hexanes togive the sub-title compound as a brown solid (0.085 g, 78%). LCMS calc.for C₂₁H₂₈F₃N₄O₆(M+H)⁺ m/z=489.2; found: 489.0.

Step 4.4-[(3S,5R)-3-[(tert-Butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]-3-[({6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylAcetate

A mixture of3-amino-4-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (0.010 g, 0.022 mmol),6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxylicacid (0.0082 g, 0.026 mmol), HATU (0.022 g, 0.057 mmol) in DMF (0.06 mL)and DIPEA (0.011 mL, 0.065 mmol) was stirred at room temperature for 1h. The mixture was quenched with 1N NaOH solution and extracted withEtOAc. The organics were combined, dried over Na₂SO₄ and concentrated togive the sub-title compound as a brown solid. LCMS calc. forC₃₆H₄₀F₆N₅O₆(M+H)⁺ m/z=752.3; found: 752.0.

Step 5.N-{4-[(3S,5R)-3-Amino-5-(trifluoromethyl)piperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxamide

A mixture of4-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]-3-[({6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (0.015 g, 0.020 mmol) in MeOH (0.8 mL), THF (0.8 mL) and 1.0 Maq. NaOH (0.8 mL, 0.8 mmol) was stirred at room temperature for 0.5 h.The solution was then concentrated under reduced pressure and theremaining aqueous phase was extracted with EtOAc. The organic extractwas concentrated to dryness under reduced pressure. The residue wastreated with 4.0 M HCl in dioxane (0.20 mL, 0.80 mmol) for 20 min. Thereaction mixture was then concentrated under reduced pressure. Theresidue was dissolved in 4.5 mL of MeOH, neutralized with NH₄OHsolution, and purified by preparative LCMS (Waters SunFire™ C18 column,19 mm×100 mm, 5 μm particle size, eluting with a gradient of MeCN/watercontaining 0.1% NH₄OH, at flow rate of 30 mL/min.) to afford twoseparated diastereoisomers of the title compound as white powders.

Diastereoisomer 1. First peak. Retention time 1.24 min., LCMS calc. forC₂₉H₃₀F₆N₅O₃(M+H)⁺ m/z=610.2; found: 610.0.

Diastereoisomer 2. Second peak. Retention time 1.32 min., LCMS calc. forC₂₉H₃₀F₆N₅O₃(M+H)⁺ m/z=610.2; found: 610.0.

The diastereoisomers correspond to the (7R) and (7S) diastereoisomers ofthe title compound,N-{4-[(3S,5R)-3-amino-5-(trifluoromethyl)piperidin-1-yl]-(7R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxamideandN-{4-[(3S,5R)-3-amino-5-(trifluoromethyl)piperidin-1-yl]-(7S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxamide.The alternative enantiomers,N-{4-[(3R,5S)-3-amino-5-(trifluoromethyl)piperidin-1-yl]-(7R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxamideandN-{4-[(3R,5S)-3-amino-5-(trifluoromethyl)piperidin-1-yl]-(7S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxamide,are prepared by an analogous route starting from using tert-butyl[(3R,5S)-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate(Enantiomer 1) from step 1.

Example 73N-{4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxamide

To a mixture of6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxylic acid (232mg, 0.492 mmol), tert-butyl[(3S,5R)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(152 mg, 0.436 mmol), and HATU (513 mg, 1.35 mmol) in DMF (3.0 mL),DIPEA (298 mg, 2.30 mmol) was added. The reaction mixture was stirred atroom temperature for 2 h, and then concentrated under reduced pressure.To the resulting residue, DCM (2.0 mL) was added followed by TFA (2.0mL). The mixture was stirred at room temperature for 30 min., and thenconcentrated under reduced pressure. The resulting residue was purifiedusing RP-HPLC (XBridge™ C18 column, eluting with a gradient ofMeCN/water containing 0.1% NH₄OH, at flow rate of 30 mL/min.) to affordthe title compound as a white solid (65.9 mg, 29%). LCMS calc. forC₂₆H₂₇F₃N₅O₃(M+H)⁺: m/z=514.2; found 514.0. ¹H NMR (500 MHz, DMSO-d₆) δ10.42 (s, 1H), 8.90 (s, 1H), 8.34 (dd, J=8.7, 4.0 Hz, 1H), 8.20 (t,J=8.8 Hz, 1H), 7.50-7.41 (m, 1H), 7.33-7.26 (m, 1H), 4.55-4.43 (m, 2H),3.93 (s, 3H), 3.35 (t, J=8.5 Hz, 2H), 3.05-2.95 (m, 1H), 2.90-2.82 (m,1H), 2.64-2.54 (m, 1H), 2.39 (t, J=10.4 Hz, 1H), 2.26 (t, J=11.2 Hz,1H), 1.64-1.51 (m, 1H), 1.41-1.17 (m, 3H), 0.64-0.55 (m, 4H) ppm.

Example 74N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxamide

To a mixture of6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxylic acid (176mg, 0.372 mmol), tert-butyl((3R,4R,5S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(152 mg, 0.317 mmol), and HATU (374 mg, 0.983 mmol) in DMF (3.0 mL)DIPEA (238 mg, 1.84 mmol) was added. The reaction mixture was stirred atroom temperature for 2 h, and then concentrated under reduced pressure.To the resulting residue, DCM (2.0 mL) was added followed by TFA (2.0mL). The mixture was stirred at room temperature for 30 min., and thenconcentrated under reduced pressure. The resulting residue was purifiedusing RP-HPLC (XBridge™ C18 column, eluting with a gradient ofMeCN/water containing 0.1% NH₄OH, at flow rate of 30 mL/min.) to affordthe title compound as a white solid (54 mg, 32%). LCMS calc. forC₂₆H₂₇F₃N₅O₄(M+H)⁺: m/z=530.2; found 530.0. ¹H NMR (500 MHz, DMSO-d₆) δ10.18 (s, 1H), 8.70 (s, 1H), 8.34 (dd, J=8.7, 4.0 Hz, 1H), 8.18 (t,J=8.8 Hz, 1H), 7.39-7.32 (m, 1H), 7.24-7.17 (m, 1H), 4.53-4.44 (m, 2H),4.41 (d, J=3.8 Hz, 1H), 3.89 (s, 3H), 3.36 (t, J=8.5 Hz, 2H), 3.10-3.04(m, 1H), 3.00-2.93 (m, 1H), 2.63 (t, J=10.8 Hz, 1H), 2.58-2.51 (m, 2H),2.46-2.38 (m, 1H), 1.66 (br, 2H), 1.48-1.36 (m, 1H), 0.69 (d, J=6.5 Hz,3H) ppm.

Example 755-Amino-N-{4-[(3R,4S,5S)-3-amino-4-hydroxy-4,5-dimethylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

Step 1. Benzyl(3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxy-4,5-dimethylpiperidine-1-carboxylate

And Benzyl(3R,4S,5S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxy-4,5-dimethylpiperidine-1-carboxylate

Benzyl(3R,55S)-3-[(tert-butoxycarbonyl)amino]-5-methyl-4-oxopiperidine-1-carboxylate(466 mg, 1.29 mmol) was added to an oven-dried vial equipped with amagnetic stirring bar. The vial was sealed with a PTFE-lined septum andkept under an N₂ atmosphere. A solution of LaCl₃.2LiCl in THF (fromAldrich, 0.6 M, 6.50 mL, 3.90 mmol) was added. The reaction mixture wasstirred at room temperature for 1 h, and then cooled to −10° C. Asolution of methylmagnesium chloride in THF (3.0 M; 1.30 mL, 3.90 mmol)was added slowly. After stirring at −10° C. for 1.5 h, the reaction wasquenched with saturated aq. NH₄Cl and the solution was extracted withEtOAc (3 times). The combined organic layers were washed with brine,dried over anhydrous Na₂SO₄, and concentrated under reduced pressure.

The resulting residue was purified using RP-HPLC (XBridge™ C18 column,eluting with a gradient of MeCN/water containing 0.05% TFA, at flow rateof 30 mL/min.) to afford benzyl(3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxy-4,5-dimethylpiperidine-1-carboxylateas a colorless oil (81 mg, 17%), Retention time 2.085 min.: LCMS calc.for C₂₀H₃₀N₂NaO₅ (M+Na)⁺: m/z=401.2; found 401.0; and benzyl(3R,4S,5S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxy-4,5-dimethylpiperidine-1-carboxylateas a colorless oil (100 mg, 21%), retention time: 2.247 min., LCMS calc.for C₂₀H₃₀N₂NaO₅ (M+Na)⁺: m/z=401.2; found 401.0.

Step 2. tert-Butyl[(3R,4S,5S)-4-hydroxy-4,5-dimethylpiperidin-3-yl]carbamate

To a stirred solution of benzyl(3R,4S,5S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxy-4,5-dimethylpiperidine-1-carboxylate(100 mg, 0.265 mmol) in MeOH (5.0 mL), 10 wt % Pd on carbon (33 mg) wasadded. The reaction mixture was stirred at room temperature under ahydrogen atmosphere (balloon pressure) for 3 h. The reaction wasfiltered through a pad of diatomaceous earth (eluted with MeOH), andthen concentrated under reduced pressure. The resulting crude productwas used directly in the next step without further purification (60 mg,92%). LCMS calc. for C₁₂H₂₅N₂O₃ (M+H)⁺: m/z=245.2; found 245.0.

Step 3. tert-Butyl [(3R,4S,5S)-4-hydroxy-4,5-dimethyl-1-(5-nitro-2,3-dihydrofuro[2, 3-b]pyridin-4-yl)piperidin-3-yl]carbamate

To a vial containing 4-iodo-5-nitro-2,3-dihydrofuro[2,3-b]pyridine (76mg, 0.26 mmol) and tert-butyl[(3R,4S,5S)-4-hydroxy-4,5-dimethylpiperidin-3-yl]carbamate (60 mg, 0.24mmol), EtOH was added (2.0 mL), followed by DIPEA (114 mg, 0.883 mmol).The mixture was stirred at 110° C. for 12 h. After cooling to roomtemperature, the reaction mixture was concentrated under reducedpressure. The resulting residue was purified on silica gel (0-100% EtOAcin hexanes) to give the sub-title compound as a yellow foamy solid (68mg, 69%). LCMS calc. for C₁₉H₂₉N₄O₆ (M+H)⁺: m/z=409.2; found 409.0.

Step 4. tert-Butyl [(3R,4S,5S)-1-(5-amino-2, 3-dihydrofuro[2,3-b]pyridin-4-yl)-4-hydroxy-4, 5-dimethylpiperidin-3-yl]carbamate

To a stirred solution of tert-butyl[(3R,4S,5S)-4-hydroxy-4,5-dimethyl-1-(5-nitro-2,3-dihydrofuro[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate(68 mg, 0.17 mmol) in MeOH (3.0 mL), 10 wt % Pd on carbon (25 mg) wasadded. The reaction mixture was stirred at room temperature under ahydrogen atmosphere (balloon pressure) for 6 h. The mixture was filteredthrough a pad of diatomaceous earth (eluted with MeOH), and thenconcentrated under reduced pressure. The resulting crude product wasused directly in the next step without further purification (62 mg,98%). LCMS calc. for C₁₉H₃₁N₄O₄ (M+H)⁺: m/z=379.2; found 379.0.

Step 5.5-Amino-N-{4-[(3R,4S,5S)-3-amino-4-hydroxy-4,5-dimethylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

To a mixture of5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylicacid (75 mg, 0.21 mmol), tert-butyl[(3R,4S,5S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-4-hydroxy-4,5-dimethylpiperidin-3-yl]carbamate(62 mg, 0.16 mmol) and HATU (196 mg, 0.515 mmol) in DMF (2.0 mL), DIPEA(123 mg, 0.952 mmol) was added. The reaction mixture was stirred at roomtemperature for 3 h, and then concentrated under reduced pressure. DCM(2.0 mL) was added to the resulting residue followed by TFA (2.0 mL).The mixture was stirred at room temperature for 30 min., and thenconcentrated under reduced pressure. The resulting residue was purifiedusing RP-HPLC (XBridge™ C18 column, eluting with a gradient ofMeCN/water containing 0.1% NH₄OH, at flow rate of 30 mL/min.) to affordthe title compound as a white solid (25 mg, 29%). LCMS calc. forC₂₄H₂₇F₂N₆O₃s (M+H)⁺: m/z=517.2; found 517.0. ¹H NMR (500 MHz, DMSO-d₆)δ 9.34 (s, 1H), 8.78 (s, 1H), 7.64-7.46 (m, 3H), 7.24 (t, J=8.6 Hz, 2H),4.47 (t, J=9.1 Hz, 2H), 3.97 (s, 1H), 3.37 (t, J=8.5 Hz, 2H), 2.87-2.79(m, 2H), 2.79-2.72 (m, 1H), 2.63 (dd, J=10.8, 4.6 Hz, 1H), 2.60-2.55 (m,1H), 1.85-1.76 (m, 1H), 1.39 (br, 2H), 0.98 (s, 3H), 0.73 (d, J=6.8 Hz,3H) ppm.

Example 765-Amino-N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-4,5-dimethylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

Step 1. tert-Butyl[(3R,4R,5S)-4-hydroxy-4,5-dimethylpiperidin-3-yl]carbamate

To a stirred solution of benzyl(3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxy-4,5-dimethylpiperidine-1-carboxylate(81 mg, 0.21 mmol) in MeOH (4.0 mL), 10 wt % Pd on carbon (29 mg) wasadded. The reaction mixture was stirred at room temperature under ahydrogen atmosphere (balloon pressure) for 3 h. The reaction mixture wasfiltered through a pad of diatomaceous earth (eluted with MeOH), andthen concentrated under reduced pressure. The resulting crude productwas used directly in the next step without further purification (46 mg,88%). LCMS calc. for C₁₂H₂₅N₂O₃ (M+H)⁺: m/z=245.2; found 245.0.

Step 2. tert-Butyl [(3R,4R,5S)-4-hydroxy-4,5-dimethyl-1-(5-nitro-2,3-dihydrofuro[2, 3-b]pyridin-4-yl)piperidin-3-yl]carbamate

To a vial containing 4-iodo-5-nitro-2,3-dihydrofuro[2,3-b]pyridine (59mg, 0.20 mmol) and tert-butyl[(3R,4R,5S)-4-hydroxy-4,5-dimethylpiperidin-3-yl]carbamate (46 mg, 0.19mmol) was added EtOH (2.0 mL), followed by DIPEA (100 mg, 0.772 mmol).The mixture was stirred at 110° C. for 15 h. After cooling to the roomtemperature, the reaction was concentrated under reduced pressure. Theresulting residue was purified on silica gel (0-100% EtOAc in hexanes)to give the sub-title compound as a yellow foamy solid (51 mg, 67%).LCMS calc. for C₁₉H₂₉N₄O₆ (M+H)⁺: m/z=409.2; found 409.0.

Step 3. tert-Butyl [(3R,4R,5S)-1-(5-Amino-2, 3-dihydrofuro[2,3-b]pyridin-4-yl)-4-hydroxy-4, 5-dimethylpiperidin-3-yl]carbamate

To a stirred solution of tert-butyl[(3R,4R,5S)-4-hydroxy-4,5-dimethyl-1-(5-nitro-2,3-dihydrofuro[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate(51 mg, 0.13 mmol) in MeOH (3.0 mL), 10 wt % Pd on carbon (19 mg) wasadded. The reaction mixture was stirred at room temperature under ahydrogen atmosphere (balloon pressure) for 6 h. The mixture was filteredthrough a pad of diatomaceous earth (eluted with MeOH), and thenconcentrated under reduced pressure. The resulting crude product wasused directly in the next step without further purification (44 mg,92%). LCMS calc. for C₁₉H₃₁N₄O₄ (M+H)⁺: m/z=379.2; found 379.0.

Step 4.5-Amino-N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-4,5-dimethylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide

To a mixture of5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylicacid (55 mg, 0.15 mmol), tert-butyl[(3R,4R,5S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-4-hydroxy-4,5-dimethylpiperidin-3-yl]carbamate(44 mg, 0.12 mmol) and HATU (134 mg, 0.353 mmol), DMF (2.0 mL) wasadded, followed by DIPEA (86 mg, 0.67 mmol). The reaction mixture wasstirred at room temperature for 3 h, and then concentrated under reducedpressure. DCM (2.0 mL) was added to the resulting residue followed byTFA (2.0 mL). The mixture was stirred at room temperature for 30 min.and then concentrated under reduced pressure. The resulting residue waspurified using RP-HPLC (XBridge™ C18 column, eluting with a gradient ofMeCN/water containing 0.1% ammonium hydroxide, at flow rate of 30mL/min.) to afford the title compound as a white solid (20 mg, 34%).LCMS calc. for C₂₄H₂₇F₂N₆O₃S (M+H)⁺: m/z=517.2; found 517.0. ¹H NMR (500MHz, DMSO-d₆) δ 9.17 (s, 1H), 8.61 (s, 1H), 7.59-7.45 (m, 3H), 7.21 (t,J=8.6 Hz, 2H), 4.52-4.42 (m, 2H), 4.06 (s, 1H), 3.37 (t, J=8.5 Hz, 2H),2.99-2.92 (m, 1H), 2.90-2.79 (m, 2H), 2.77-2.64 (m, 2H), 1.93-1.82 (m,1H), 1.46 (br, 2H), 0.92 (s, 3H), 0.71 (d, J=6.9 Hz, 3H) ppm.

Example A. Pim Enzyme Assays

Pim-1 and Pim-3 kinase assays—20 μL reactions were run in white 384 wellpolystyrene plates dotted with 0.8 μcompound/DMSO in the assay buffer(50 mM Tris, pH 7.5, 0.01% Tween-20, 5 mM MgCl₂, 0.01% BSA, 5 mM DTT),containing 0.05 μM Biotin-labeled BAD peptide substrate (AnaSpec 62269),1 mM ATP, and 2.5 pM (Pim-1, Invitrogen PV3503) or 1.25 pM (Pim-3,Millipore 14-738) enzyme for 1 h at 25° C. Reactions were stopped byaddition of 10 μL STOP Buffer (150 mM Tris, pH=7.5, 150 mM NaCl, 75 mMEDTA, 0.01% Tween-20, 0.3% BSA) supplemented with Phospho-Bad (Ser112)Antibody (Cell Signaling 9291) diluted 666-fold, and Streptavidin donorbeads (PerkinElmer 6760002) along with Protein-A acceptor beads(PerkinElmer 6760137) at 15 μg/mL each. Supplementation of the STOPbuffer with beads and stopping the reactions were done under reducedlight. Prior to the stopping reactions STOP buffer with beads waspre-incubated for 1 h in the dark at room temperature. After stoppingthe reactions, plates were incubated for 1 h in the dark at roomtemperature before reading on a PHERAstar FS plate reader (BMG Labtech)under reduced light.

Pim-2 kinase assay—20 μL reactions were run in white 384 wellpolystyrene plates dotted with 0.8 μL compound/DMSO in the assay buffer(50 mM Tris, pH 7.5, 0.01% Tween-20, 5 mM MgCl₂, 0.01% BSA, 5 mM DTT),containing 0.05 μM Fluorescein-labeled CREBtide peptide substrate(Invitrogen PV3508), 1 mM ATP, and 1 nM enzyme (Invitrogen PV3649) for 2h at 25° C. Reactions were stopped by addition of 10 μL TR-FRET DilutionBuffer (Invitrogen PV3574) with 30 mM EDTA and 1.5 nM LanthaScreenTb-CREB pSer133 antibody (Invitrogen PV3566). After 30 min. incubationat room temperature, plates were read on a PHERAstar FS plate reader(BMG Labtech).

Compounds of the invention having an IC₅₀ of 2 μM or less when testedfor PIM kinase activity under the assay conditions disclosed above areconsidered active.

Although the above in vitro assays are conducted at 1 mM ATP compoundscan also be evaluated for potency and in vitro activity against PIMtargets utilizing K_(m) conditions, where the concentration of ATP isset to the K_(m) value and the assay is more sensitive to PIM inhibitionactivity.

Example B. Pim Cellular Assays

One or more compounds of the invention were tested for inhibitoryactivity of PIM according to at least one of the following cellularassays. Compounds of the invention having an IC₅₀ of 10 μM or less whentested for PIM kinase activity under the cellular assay conditionsdisclosed below would be and were considered active.

Pim Cell Proliferation Assays

KG-1A cells are purchased from ATCC (Manassas, Va.) and KMS.12.BM cellsare purchased from NIBIO, JCRB cell bank (Tokyo, Japan) and maintainedin the culture mediums recommended, RPMI, 10% FBS (Roswell Park MemorialInstitute 1640 Medium supplemented with 10% fetal bovine serum) and IMDM20% FBS (Iscove's Modified Dulbecco's Medium (MDM) with 20% fetal bovinestrum) (Mediatech, Manassas, Va.) respectively. To measure theanti-proliferation activity of test compounds, both cell lines areplated with the culture medium (2×10³ cells/well/in 200 μL) into 96-wellpolystyrene ultralow binding (Costar®) in the presence or absence of aconcentration range of test compounds. After 4 days, [³H]-thymidine, 1μCi/10 μL/well (PerkinElmer, Boston, Mass.) in culture medium is thenadded to the cell culture for an additional 16 h before the incorporatedradioactivity is separated by filtration with a Packard MicroplateHarvester with water through a 0.3% polyethylenimine pre-wetted glassfiber GF/B filter plates (Packard Bioscience/PerkinElmer, Boston,Mass.). The plate is measured by liquid scintillation counting with aTopCount® scintillation sounter (PerkinElmer). IC₅₀ determination isperformed by fitting the curve of percent inhibition versus the log ofthe inhibitor concentration using GraphPad Prism® 5.0 software.

Pim pBAD Signaling Assays

KG-1A cells are purchased from ATCC (Manassas, Va.) and KMS.12.BM cellsare purchased from NIBIO, JCRB cell bank (Tokyo, Japan) and maintainedin the culture mediums recommended, RPMI, 10% FBS and IMDM 20% FBS(Mediatech, Manassas, Va.) respectively. To measure the pBAD inhibitoryactivity of the compounds, both cell lines are plated with the culturemedium (1×10⁶/well/100 μL for KG1A and 4×10⁵ cells/well/in 100 μL forKMS12BM) into 96-well V bottom polypropylene plates (Matrix, ThermoFisher, USA) and incubated 30 min. at 37° C. to normalize cell signalingfrom handling. Test compounds are added at an appropriate concentrationrange and further incubated for 2.5 h for KMS.12.BM cells and 4 h forKG1-A cells. Plates are centrifuged at 2000 RPM for 10 min. andsupernatants aspirated. 100 μL lysis buffer with protease inhibitors(Cell Signaling Technologies, Danver, Mass., Sigma, St Louis Mo., EMD,USA) is added to the pellets, mixed well and set on ice for 30 min.Lysates are frozen overnight at −80° C. To measure the pBAD activity, aCell Signaling ELISA (enzyme-linked immunosorbent assay) kit (CellSignaling Path Scan phosphor pBAD ELISA) is utilized. 50 μL of thelysate is tested per the ELISA protocol and the data analysis isperformed by software on a SpectraMax® M5 plate reader (MolecularDevices, Sunnyvale, Calif.). IC₅₀ determination is performed by fittingthe curve of percent inhibition versus the log of the inhibitorconcentration using GraphPad Prism® 5.0 software.

Data obtained for the Example compounds, obtained using the methodsdescribed in Example A, are provided in Table 1.

TABLE 1 Pim Enzyme Assay Data Example Pim1 IC₅₀ (nM) Pim2 IC₅₀ (nM) Pim3IC₅₀ (nM)  1 +    277  +  2 >40 >2000¹ >40  3 + + +  4 + >2000  + 5 + + +  6 + >2000  +  7 + + +  8 + >2000  +  9 + + + 10 + ++ + 11 +++ + 12 + + + 13 + >2000  + 14 + + + 15 (Diastereoisomer 1) + + + 15(Diastereoisomer 2) + + + 16 (Diastereoisomer 1) + >2000  + 16(Diastereoisomer 2) + >2000  + 17 + ++ + 18 (Diastereoisomer 1) + ++ +18 (Diastereoisomer 2) + ++ + 19 (Diastereoisomer 1) + >2000  ++ 19(Diastereoisomer 2) + ++ + 20 + + + 21 + + + 22 (Diastereoisomer 1) +++ + 22 (Diastereoisomer 2) + + + 23 (Diastereoisomer 1) + + + 23(Diastereoisomer 2) + + + 24 + >2000  + 25 + + + 26 + >2000  + 27 + + +28 + + + 29 + ++ + 30 + ++ + 31 + + + 32 + + + 33 + ++ + 34 + >2000  +35 >40 >2000² >40 36 + + + 37 (mixture of + + + diastereoisomers) 37(Diastereoisomer 1) + + + 37 (Diastereoisomer 2) + + + 38 + + + 39 + + +40 + + + 41 + + + 42 + + + 43 + + + 44 (Diastereoisomer 1) + + + 44(Diastereoisomer 2) + + + 45 (Diastereoisomer 1) + + + 45(Diastereoisomer 2) + + + 46 (Diastereoisomer 1) + + + 46(Diastereoisomer 2) + + + 47 (Diastereoisomer 1) + + + 47(Diastereoisomer 2) + + + 48 (Diastereoisomer 1) + ++ + 48(Diastereoisomer 2) + + + 49 (Diastereoisomer 1) + + + 49(Diastereoisomer 2) + + + 50 + ++ + 51 (Diastereoisomer 1) + + + 51(Diastereoisomer 2) + + + 52 + + + 53 (Diastereoisomer 1) + + + 53(Diastereoisomer 2) + + + 54 (Diastereoisomer 1) + + + 54(Diastereoisomer 2) + + + 55 (Diastereoisomer 1) + ++ + 55(Diastereoisomer 2) + + + 56 (Diastereoisomer 1) + + + 56(Diastereoisomer 2) + + + 57 + ++ + 58 (Diastereoisomer 1) + ++ + 58(Diastereoisomer 2) + ++ + 59 (Diastereoisomer 1) + ++ + 59(Diastereoisomer 2) + ++ + 60 (Diastereoisomer 1) + ++ + 60(Diastereoisomer 2) + ++ + 61 (Diastereoisomer 1) + >2000  >40 61(Diastereoisomer 2) + ++ + 62 (Diastereoisomer 1) + ++ + 62(Diastereoisomer 2) + ++ + 63 (Diastereoisomer 1) + + + 63(Diastereoisomer 2) + + + 63 (Diastereoisomer 3) + + + 63(Diastereoisomer 4) + + + 64 (Diastereoisomer 1) + + + 64(Diastereoisomer 2) + + + 65 + + + 66 (Diastereoisomer 1) + + + 66(Diastereoisomer 2) + + + 67 (Diastereoisomer 1) + + + 67(Diastereoisomer 2) + + + 68 (Diastereoisomer 1) + + + 68(Diastereoisomer 2) + + + 69 + + + 70 (Diastereoisomer 1) + + + 70(Diastereoisomer 2) + + + 71 + + + 72 (Diastereoisomer 1) + + + 72(Diastereoisomer 2) + + + 73 + + + 74 + + + 75 + + + 76 + + + 1000 nM <IC₅₀ ≤ 10000 nM: +++ 100 nM < IC₅₀ ≤ 1000 nM: ++ IC₅₀ ≤ 100 nM: +.^(1, 2)Compound 2 inhibited Pim2 (100 nM < IC₅₀ ≤ 1000 nM) and compound35 inhibited PIM2 (1000 nM < IC₅₀ ≤ 10000 nM) at K_(m) ATP concentrationrather than at 1 mM concentration.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including withoutlimitation all patent, patent applications, and publications, cited inthe present application is incorporated herein by reference in itsentirety.

What is claimed is:
 1. A method of treating cancer, wherein the canceris prostate cancer, colon cancer, esophageal cancer, hepatic cancer,pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancer ofthe head or neck, glioblastoma, sarcoma, bladder cancer, lymphoma,leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia,chronic lymphocytic leukemia, chronic myelogenous leukemia, diffuselarge-B cell lymphoma, mantle cell lymphoma, non-Hodgkin lymphoma,Hodgkin lymphoma or multiple myeloma, and wherein the cancer is a cancerwherein the expression or activity of at least one of Pim1, Pim2 andPim3 is upregulated; an oncogene is activated; or Myc or BCL2 isactivated, comprising administering to a patient in need of suchtreatment a therapeutically effective amount of a compound, wherein thecompound isN-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide,a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,and a therapeutically effective amount of an anti-cancer agent, whereinthe anti-cancer agent is selected from abarelix, aldesleukin,alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole,arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene,bleomycin, bortezombi, bortezomib, busulfan intravenous, busulfan oral,calusterone, capecitabine, carboplatin, carmustine, cetuximab,chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide,cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib,daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane,docetaxel, doxorubicin, dromostanolone propionate, eculizumab,epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide,exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine,fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumabozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan,idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a,irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin,leuprolide acetate, levamisole, lomustine, meclorethamine, megestrolacetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycinC, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine,nofetumomab, oxaliplatin, paclitaxel, pamidronate, panitumumab,pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin,pipobroman, plicamycin, procarbazine, quinacrine, rasburicase,rituximab, sorafenib, streptozocin, sunitinib, sunitinib maleate,tamoxifen, temozolomide, teniposide, testolactone, thalidomide,thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab,tretinoin, uracil mustard, valrubicin, vinblastine, vincristine,vinorelbine, vorinostat and zoledronate.
 2. The method of claim 1,wherein the compound isN-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamideor a pharmaceutically acceptable salt thereof.
 3. The method of claim 1,wherein the compound isN-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamideor a pharmaceutically acceptable salt thereof.
 4. The method of claim 1,wherein the compound isN-{4-[(3R,4R,5S,7R)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamideor a pharmaceutically acceptable salt thereof.
 5. The method of claim 1,wherein the compound isN-{4-[(3R,4R,5S,7S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamideor a pharmaceutically acceptable salt thereof.
 6. The method of claim 1,wherein the cancer is prostate cancer.
 7. The method of claim 1, whereinthe cancer is pancreatic cancer.
 8. The method of claim 1, wherein thecancer is acute myelogenous leukemia.
 9. The method of claim 1, whereinthe cancer is diffuse large-B cell lymphoma.
 10. The method of claim 1,wherein the cancer is multiple myeloma.
 11. The method of claim 1,wherein the cancer is selected from acute myelogenous leukemia anddiffuse large-B cell lymphoma, and wherein the anti-cancer agent iscytarabine, azacitidine, carmustine or lomustine.
 12. The method ofclaim 1, wherein the cancer is colon cancer.
 13. The method of claim 1,wherein the cancer is esophageal cancer.
 14. The method of claim 1,wherein the cancer is hepatic cancer.
 15. The method of claim 1, whereinthe cancer is gastric cancer.
 16. The method of claim 1, wherein thecancer is breast cancer.
 17. The method of claim 1, wherein the canceris lung cancer.
 18. The method of claim 1, wherein the cancer is acancer of the head or neck.
 19. The method of claim 1, wherein thecancer is glioblastoma.
 20. The method of claim 1, wherein the cancer issarcoma.
 21. The method of claim 1, wherein the cancer is bladdercancer.
 22. The method of claim 1, wherein the cancer is lymphoma. 23.The method of claim 1, wherein the cancer is leukemia.
 24. The method ofclaim 1, wherein the cancer is acute lymphoblastic leukemia.
 25. Themethod of claim 1, wherein the cancer is chronic lymphocytic leukemia.26. The method of claim 1, wherein the cancer is chronic myelogenousleukemia.
 27. The method of claim 1, wherein the cancer is mantle celllymphoma.
 28. The method of claim 1, wherein the cancer is non-Hodgkinlymphoma.
 29. The method of claim 1, wherein the cancer is Hodgkinlymphoma.